Elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome patients with tenascin-X mutations

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders with characteristic skin and joint involvement. The concept that EDS is a disease of fibrillar collagen was challenged by the identification of a clinically distinct, recessive type of EDS caused by deficiency of the extracellular matrix protein tenascin-X (TNX). Interestingly, haploinsufficiency of TNX is associated with the dominantly inherited hypermobility type of EDS. In this study, we examined whether missense mutations in the TNX gene can account for some of the cases of hypermobility type EDS. Furthermore, we studied whether missense mutations or heterozygosity for truncating mutations in the TNX gene lead to alterations in the dermal connective tissue. Sequence analysis revealed three missense mutations in TNX in hypermobility type EDS patients, which were not present in 192 control alleles. Morphometric analysis of skin biopsies of these patients showed altered elastic fibers in one of them, suggesting that this missense mutation is disease causing. Light microscopic and ultrastructural changes of the elastic fibers were observed in TNX-haploinsufficient hypermobility type EDS patients, which were not found in hypermobility type EDS patients in whom TNX mutations were excluded. Our results indicate that the observed alterations in elastic fibers are specific for hypermobility type EDS patients with mutations of TNX.     

Tenascin-X,collagen, and Ehlers–Danlos syndrome: Tenascin-X gene defects can protect against adverse cardiovascular events

Long thought to be two separate syndromes, Ehlers–Danlos syndrome hypermobility type (EDS-HT) and benign joint hypermobility syndrome (BJHS) appear on close examination to represent the same syndrome, with virtually identical clinical manifestations. While both EDS-HT and BJHS were long thought to lack the genetic loci of other connective tissue disorders, including all other types of EDS, researchers have discovered a genetic locus that accounts for manifestations of both EDS-HT and BJHS in a small population of patients. However, given the modest sample size of these studies and the strong correlation between serum levels of tenascin-X with clinical symptoms of both EDS-HT and BJHS, strong evidence exists for the origins of both types of hypermobility originating in haploinsufficiency or deficiency of the gene TNXB, responsible for tenascin-X.     

Hypermobile Ehlers-Danlos syndromes: Complex phenotypes,challenging diagnoses,and poorly understood causes

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.     

DSE associated musculocontractural EDS,a milder phenotype or phenotypic variability

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is an autosomal recessive condition characterized by distinct craniofacial features, multisystem congenital malformations and progressive fragility of connective tissues. It is caused by pathogenic variants in CHST14 and DSE genes. There are three reports of pathogenic variants in DSE in four mcEDS patients. In this study we provide clinical and molecular presentation of two new patients with DSE related mcEDS.Analysing clinical exome data, a homozygous pathogenic DSE variant, c.1150_1157del p.(Pro384Trpfs*9), was identified in a 32 year old man with bilateral congenital talipes equinovarus, characteristic facial features, myopia, hyperextensible skin at the elbows, significant palmar wrinkling, bilateral inguinal hernias and chronic leg, back and joint pain. Electron microscopical examination of skin biopsy showed changes consistent with mild compensatory elastic fibre hypertrophy and mildly loose collagen bundles.The variant is predicted to result in a frameshift and introduction of a premature termination codon in the final exon of the DSE gene, anticipated to lead to the loss of approximately 60% of the normal reading frame. The second patient has a phenotype consistent with previously reported cases of DSE associated musculocontractural EDS. A novel homozygous missense DSE variant of uncertain clinical significance was detected.This case study further delineates the DSE associated mcEDS phenotype and illustrates absence of major cutaneous, cardiovascular, renal and respiratory features, which supports previous suggestions that patients with DSE associated mcEDS present with a milder phenotype compared to those with CHST14 mutations.     

Ehlers-Danlos综合征及其致病基因研究进展

Ehlers-Danlos综合征(Ehlers-Danlos syndtome,EDS) 一组罕见的遗传性结缔组织疾病,共同的临床特征为皮肤弹性过度、脆性增加、创伤后愈合延迟、形成萎缩性瘢痕及泛发的关节运动过度.该病分为6个临床类型,其遗传方式不同、临床表现多样.分子遗传学研究显示,本病的发生与COL5A1、COL5A2、TNXB、COL3A1、PLOD1、COL1A1、COL1A2和ADAMTS-2等基因有关.     

Genome damage in children with classical Ehlers-Danlos syndrome - An in vivo and in vitro study

Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility with prevalence 1:20 000. Its incidence is probably underestimated due to unknown number of subjects having mild symptoms who may have never been diagnosed through entire life time. Classical EDS is characterized by pathogenic variants of genes encoding type V collagen. The biological effects and health risks of patients with EDS exposure to low doses of ionizing radiation is poorly understood. The aim of this study was to investigate biological effect of low doses of ionizing radiation in children with EDS. Background values of chromosome aberrations in children suffering from classical EDS were determined and compared with control subjects. The in vitro experiment was performed by γ-irradiation of blood lymphocytes from EDS patients and healthy subjects at low doses (0.1, 0.2 and 0.3 Gy). Results show a significant increase level of spontaneous and radiation-induced chromosomal aberrations in children suffering from EDS in comparison with the control subjects (p < 0.05). In conclusion, children with EDS express higher background chromosome aberration frequency and increased radiosensitivity. These findings suggest specific susceptibility of EDS patients and importance of future investigation on risks of diagnostics and therapy which include radiation and genotoxic agents.     

A sporadk case of Ehlers-Danlos syndrome type IV Diagnosed by a morphometric study of collagen content

A sporadic cam of a young woman with Ehlers-Danlos syndrome (EDS) type IV is hscrlbed. Multiple aneurysms of medium-sized arteries were noted. Histological study revealed deposition of acid mucopolysaccharides in the media of malor arteries and in the intirna of smaller arteries with Intimal thickenlng. Systemic changes related to stenosis were observed in arteries more than 100 μm in diameter. Histologic study revealed hyperplasia of adipocytes in the submucosal layer of the intestines and the trachea, and flbrosis of Langerhans' islets of the pancreas. Typical signs for EDS such as skin hyperelasticity and joint hypermobility, and posltive family history were not present. However, type III collagen was not detected on frozen sections from either the skin or the anterior cerebral artery by imrnunohistochem-ical quantification. Thus, it was concluded that the present case is a varlant of EDS.     

Cardiac valvular Ehlers‐Danlos syndrome is a well‐defined condition due to recessive null variants in COL1A2

Cardiac valvular Ehlers‐Danlos syndrome (EDS) is a rare EDS subtype, caused by specific recessive variants in the gene encoding pro‐α2‐chain of type I collagen (COL1A2). Cardiac valvular EDS is mainly characterized by generalized/peripheral joint hypermobility, moderate–severe cardiac valvular disease, skin hyperextensibility and other minor soft tissues features. Only five molecularly confirmed patients have been reported to date. Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant in COL1A2. Clinical data and literature review allowed to better define the clinical spectrum of cardiac valvular EDS which now emerges as a more recognizable EDS variant with progressive heart valve disease firstly affecting the mitral valve. Possibly distinguishing features include bilateral flatfeet with hindfoot pronation, lower eyelid ptosis and hypoplasia of the interphalangeal creases. The absence of bone fragility in our patients indicates that cardiac valvular EDS is also separated from patients with autosomal recessive osteogenesis imperfecta and variants in COL1A2, as well as from individuals with autosomal dominant osteogenesis imperfecta and severe cardiac valvular disease.     

Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome

Skin hyperelasticity, tissue fragility with atrophic scars, and joint hypermobility are characteristic for the classical type of Ehlers-Danlos syndrome (EDS). The disease is usually inherited as an autosomal dominant trait; however, recessive mode of inheritance has been documented in tenascin-X-deficient EDS patients. Mutations in the genes coding for collagen alpha1(V) chain (COL5A1), collagen alpha2(V) chain (COL5A2), tenascin-X (TNX), and collagen alpha1(I) chain (COL1A1) have been characterized in patients with classical EDS, thus confirming the suspected genetic heterogeneity. Recently, we described a patient with severe classical EDS due to a Gly1489Glu substitution in the alpha1(V) triple-helical domain who was, in addition, heterozygous for a disease-modifying Gly530Ser substitution in the alpha1(V) NH(2)-terminal domain [Giunta and Steinmann, 2000: Am. J. Med. Genet. 90:72-79; Steinmann and Giunta, 2000: Am. J. Med. Genet. 93:342]. Here, we report on a 4-year-old boy with mild classical EDS, born to healthy consanguineous Turkish parents; the mother presented a soft skin, while the father had a normal thick skin. Ultrastructural analysis of the dermis revealed in the patient the typical "cauliflower" collagen fibrils, while in both parents variable moderate aberrations were seen. Mutation revealed the presence of a homozygous Gly530Ser substitution in the alpha1(V) collagen chains in the patient, while both parents were heterozygous for the same substitution. An additional mutation in either the COL5A1 and COL5A2 genes was excluded. Furthermore, haplotype analysis with polymorphic microsatellite markers excluded linkage to the genes coding for alpha3(V) collagen (COL5A3), tenascin-X (TNX), thrombospondin-2 (THBS2), and decorin (DCN). These new findings support further our previous hypothesis that the heterozygous Gly530Ser substitution is disease modifying and now suggest that in the homozygous state it is disease causing.     

Aortic root dilatation in Ehlers-Danlos syndrome types I, II and III A report of five cases

We have identified five families in whom individuals affected with the Ehlers-Danlos syndrome (EDS) types I, II or III had aortic root dilatation (ARD). All propositi had a low upper/lower segment ratio but no other diagnostic skeletal or ocular features of Marfan syndrome. Their skin had the soft, velvety texture characteristic of EDS and all had significant joint laxity. Probands included a 4-year-old girl with EDS type I, 4-and 8-year-old girls with EDS type HI, a 35-year-old male with EDS type II, and a 51-year-old female with EDS type III. Review of these cases suggests the need for multicenter clinical studies in order to determine the prevalence and the rate of progression of ARD in EDS types I, II, and III. Such studies are necessary to determine whether echocardiograms (including measurement of aortic root diameter) should be considered on initial evaluation of all patients with mild forms of EDS.     

Third case of a distinct variant of the Ehlers-Danlos Syndrome (EDS)

A 16-year-old boy was diagnosed as having EDS. Analysis of this patient together with two previously reported cases supported a distinct variant of the EDS, probably caused by an autosomal dominant mutation.     

Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI

The Ehlers-Danlos syndromes are a heterogeneous group of inherited connective tissue disorders that are characterized by joint hypermobility and skin fragility and hyperextensibility. Patients with the autosomal recessive type VI variant of the Ehlers-Danlos syndromes (EDS VI), also classified as the kyphoscoliotic type, are clinically characterized by neonatal kyphoscoliosis, generalized joint laxity, skin fragility, and severe muscle hypotonia at birth. Biochemically, this has been attributed to a deficiency of lysyl hydroxylase (LH), an important posttranslational modifying enzyme in collagen biosynthesis. This enzyme hydroxylates specific lysine residues in the collagen molecule to form hydroxylysines which have two important functions. The residues serve as attachment sites for galactose and glucosylgalactose and they also act as precursors of the crosslinking process that gives collagen its tensile strength. At least 20 different mutations have been identified in the LH1 gene (the originally described form) that contribute to LH deficiency and the clinical characteristics of EDS VI. Two of these mutations, a large duplication of exons 10-16, arising from a homologous recombination of intronic Alu sequences, and a nonsense mutation, Y511X, in exon 14 of the LH1 gene, have been identified in five or more unrelated patients. Both mutations appear to have originated from a single ancestral gene. Alternative processing pathways involving alternate splicing and mRNA degradation, which reduce the effect of the mutant allele and restore partial activity of the enzyme, have been identified. A second class of EDS VI has been proposed in which patients have the clinical phenotype of EDS VI but their levels of LH activity are normal. The biochemical basis for this form of EDS VI is currently unknown.     

Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen

Ehlers-Danlos syndrome (EDS) type VII results from defects in the conversion of type I procollagen to collagen as a consequence of mutations in the substrate that alter the protease cleavage site (EDS type VIIA and VIIB) or in the protease itself (EDS type VIIC). We identified seven additional families in which EDS type VII is either dominantly inherited (one family with EDS type VIIB) or due to new dominant mutations (one family with EDS type VIIA and five families with EDS type VIIB). In six families, the mutations alter the consensus splice junctions, and, in the seventh family, the exon is deleted entirely. The COL1A1 mutation produced the most severe phenotypic effects, whereas those in the COL1A2 gene, regardless of the location or effect, produced congenital hip dislocation and other joint instability that was sometimes very marked. Fractures are seen in some people with EDS type VII, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. These new findings expand the array of mutations known to cause EDS type VII and provide insight into genotype/phenotype relationships in these genes. Am. J. Med. Genet. 72:94–105, 1997. © 1997 Wiley-Liss, Inc.     

Management of pain and fatigue in the joint hypermobility syndrome (a.k.a. Ehlers-Danlos syndrome, hypermobility type): principles and proposal for a multidisciplinary approach

Joint hypermobility syndrome (JHS), or Ehlers-Danlos syndrome (EDS) hypermobility type (EDS-HT), is a underdiagnosed heritable connective tissue disorder characterized by generalized joint hypermobility and a wide range of visceral, pelvic, neurologic, and cognitive dysfunctions. Deterioration of quality of life is mainly associated with pain and fatigue. Except for the recognized effectiveness of physiotherapy for some musculoskeletal features, there are no standardized guidelines for the assessment and treatment of pain and fatigue. In this work, a practical classification of pain presentations and factors contributing in generating painful sensations in JHS/EDS-HT is proposed. Pain can be topographically classified in articular limb (acute/subacute and chronic), muscular limb (myofascial and fibromyalgia), neuropathic limb, back/neck, abdominal and pelvic pain, and headache. For selected forms of pain, specific predisposing characteristics are outlined. Fatigue appears as the result of multiple factors, including muscle weakness, respiratory insufficiency, unrefreshing sleep, dysautonomia, intestinal malabsorption, reactive depression/anxiety, and excessive use of analgesics. A set of lifestyle recommendations to instruct patients as well as specific investigations aimed at characterizing pain and fatigue are identified. Available treatment options are discussed in the set of a structured multidisciplinary approach based on reliable outcome tools.     

A distinct variant of the Ehlers-Danlos syndrome

Two unrelated males presented a distinct syndrome, consisting mainly of mental retardation, short stature, wrinkled facies, curly and fine hair, scanty eyebrows and eyelashes, telecanthus, periodontitis, hypermobility of the joints, hyperextensibility and fragility of the skin, multiple nevi, papiraceous scars, bruisability, varicose veins, pectus excavatum, winged scapulae, pes planus and bilateral cryptorchidism. Since some features were typical of Ehlers-Danlos Syndrome (EDS), the clinical data were analyzed comparatively with the different types of EDS. The individualization of a distinct variant is concluded. Increased paternal age at the birth of both cases suggests a de novo dominant mutation.     

Decreased expression of lysyl hydroxylase 2 (LH2) in skin fibroblasts from three Ehlers-Danlos patients does not result from mutations in either the coding or proximal promoter region of the LH2 gene

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders characterized by tissue fragility, hyperelasticity of the skin and joint hypermobility. This phenotype, accompanied by kyphoscoliosis and/or ocular fragility, is present in patients with the autosomal recessive type VI form of EDS. These patients have significantly decreased levels of lysyl hydroxylase (LH) activity, due to mutations in the LH1 gene. LH hydroxylates specific lysine residues in the collagen molecule that are precursors for the formation of cross-links which provide collagen with its tensile strength. No disorder has been directly linked to decreased expression of LH2 and LH3, two other isoforms of LH. This study describes 3 patients with mixed phenotypes of EDS, who have significantly decreased mRNAs for LH2, but normal levels of LH1 and LH3 mRNAs, in their skin fibroblasts. In contrast to the effect of LH1 deficiency in EDS VI patients, the decreased expression of LH2 does not affect LH activity, bifunctional collagen cross-links (measured after reduction as dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL)), or helical lysine hydroxylation in these cell lines. Sequence analysis of full length LH2 cDNAs and 1kb of the promoter region of LH2 does not show mutations that could explain the decreased expression of LH2. These results suggest that the deficiency of LH2 in these fibroblasts may be caused by changes in other factors required for the expression of LH2.     

A family with Classical Ehlers-Danlos Syndrome (cEDS), mild bone fragility and without vascular complications,caused by the p.Arg312Cys mutation in COL1A1

The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT) with joint hypermobility, skin hyperextensibility and tissue fragility, which were recently re-classified (2017 International Classification). Most patients (>90%) with Classical Ehlers-Danlos syndrome (cEDS) have a mutation in the COL5A1 or COL5A2 genes encoding type V procollagen. A small number of patients with the p.Arg312Cys mutation in COL1A1 have been reported with overlapping features of both cEDS and vascular EDS (vEDS). In this report, we describe two patients from a large family with this mutation and clinical features consistent with cEDS without vascular complications. The proband presented with congenital hip dislocation (previously reported in one patient), the mother of the proband with multiple fractures in childhood, and dental defects (novel findings). The small number of patients reported with this mutation and proportion with vascular complications suggests that vascular surveillance should still be recommended.     

A classical Ehlers-Danlos syndrome family with incomplete presentation diagnosed by molecular testing

The 2017 EDS revised nosology indicates that minimal criteria suggestive for classical Ehlers-Danlos syndrome (cEDS) are skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility (gJHM) and/or at least three minor criteria that include cutaneous features and gJHM complications. Confirmatory molecular testing is obligatory to reach a final diagnosis. Although the large majority of the patients presents with these clinical features, some do not and might remain undiagnosed or misdiagnosed. Here we describe a family with 2 affected members, a 23-year-old proposita and her 51-year-old mother, who presented subtle cutaneous signs, including a variable degree of skin hyperextensibility without extensive widened atrophic scars that apparently better fitted with the overlapping hypermobile EDS. The proposita also presented gastrointestinal symptoms secondary to aberrant mast cells mediators release, making the clinical picture even more puzzling. Both patients were diagnosed by molecular testing that revealed a COL5A1 splice mutation. This report highlights the relevance of molecular analysis in patients presenting rather mild signs of EDS, especially in familial cases, and the importance of clinical expertise to make such a diagnosis.