Search Results (22)

Diagnosing hypermobility disorders and Ehlers-Danlos syndrome (EDS) in children is challenging due to overlapping features with generalized joint hypermobility (GJH) and the lack of biomarkers. Background/Objectives: This study aims to describe the clinical and genetic features of pediatric EDS patients and identify key comorbidities and correlations. Methods: This is a single-center observational study of patients under 18 diagnosed with suspicion of EDS (2018–2024) at a tertiary pediatric hospital. Diagnoses were made using 2017 criteria. Results: Forty-one patients (46% female; mean age 11.1 ± 2.8 years) were included. Based on 2017 criteria, 61% had hypermobile EDS (hEDS)/hypermobility spectrum disorder (HSD), 22% classical EDS, 7.3% vascular, and 9.7% other subtypes. Musculoskeletal (90.2%), cutaneous (68.3%), and psychiatric (56.1%) symptoms were most frequent. Significant associations included older age with psychiatric symptoms (p = 0.029), Beighton score with dislocations (p = 0.026), and less atrophic scarring in hEDS (p < 0.008). Genetic testing (73% performed) confirmed pathogenic variants (11 novel) in EDS with a known molecular cause. Conclusions: This study proposes a clinically guided approach and diagnostic algorithm for youth hypermobility, emphasizing precision medicine principles, while highlighting the urgent need for further research to identify hEDS biomarkers. Full article

Background: The purpose of this study was to assess bone densitometry parameters in patients with classical and hypermobile Ehlers-Danlos syndrome (EDS) and to determine whether the hypermobile subtype increases the risk of low bone mass, which is particularly important in this patient group, since the genetic mutation responsible for this subtype is still unknown. Material and Methods: In order to conduct this study, we collaborated with the EDS society in Poland. A total of 30 females of reproductive age who were included in the study were divided into two groups: Group 1—those with classical EDS (n = 9) and Group 2—those with hypermobile EDS (n = 21). Routine laboratory test results, bone turnover markers, and densitometry parameters were evaluated and compared. Results: The study groups showed no differences in terms of densitometry parameters or markers of calcium-phosphate metabolism. A multivariate logistic analysis demonstrated no increase in the risk of low bone mass (defined as a Z-score lower than −2) in patients with hypermobile EDS (OR 0.067 [95% Cl 0.0–20.927]; p = 0.356). Conclusions: The hypermobile subtype of EDS does not increase the risk of low bone mass; there were no significant differences between patients with hypermobile EDS and those with classical EDS in terms of either densitometry parameters or markers of calcium-phosphate metabolism. Although patients with hypermobile EDS are not at a higher risk of developing low bone mineral density, they should be regularly monitored for any calcium and phosphate metabolism abnormalities. Full article

Recently, an autosomal recessive subtype of connective tissue disorder within the spectrum of Ehlers–Danlos syndrome (EDS), named classical-like EDS type 2 (clEDS2), was identified. clEDS2 is associated with biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, specifically, affecting its aortic carboxypeptidase-like protein (ACLP) isoform. We described the 15th patient (13th family) diagnosed with clEDS2. This patient presented with notable similarities in phenotype to the documented cases, along with additional characteristics such as significant prematurity and short stature. An EDS sequencing panel-based analysis revealed homozygous AEBP1: NM_001129.5:c.2923del, p.Ala975Profs*22 likely pathogenic variants, and maternally inherited heterozygous COL11A1: NM_001854.4:c.1160A>G, p.Lys387Arg variant of uncertain significance in our patient. Upon comprehensive review of all previously reported clEDS2 patients, our patient exhibited the following overlapping phenotypes, including cutaneous features: hyperextensibility, atrophic scars/delayed wound healing (100%), easy bruising (100%), excessive skin (93%); skeletal features: generalized joint hypermobility (93%), pes planus (93%), dislocation/subluxation (93%); and cardiovascular features (86%). Our patient did not display symptoms of the critical complications reported in a few individuals, including superior mesenteric artery aneurysms and ruptures, aortic root aneurysm/dissection, spontaneous pneumothoraxes, and bowel ruptures. Together, this case expands the genetic and clinical phenotypic spectrum of AEBP1-related clEDS2. Full article

Patients with Ehlers-Danlos Syndrome (EDS) frequently suffer from severe chronic pain. We carried out an observational cohort study to assess the effectiveness of compression garments (CGs) for reducing this pain. Patients with non-vascular EDS were given custom-made Cerecare^® CGs during a visit to a specialist clinic (visit V0). They were followed up over 2 years with visits every 6 months (V1–V4). At each visit, pain was assessed for the joints treated with CGs using a visual analogue scale (VAS; 0–100 mm). Additional measures were obtained to assess neuropathic pain (painDETECT questionnaire), proprioception/balance (Berg Balance Scale), and functional independence, amongst others. Data were analyzed for 67 patients with EDS (hypermobile: 91%; classical: 6%; kyphoscoliotic: 3%). For the most painful joint, the mean VAS rating was 71.5 ± 22.8 mm at V0; this decreased to 53.5 ± 25.5 mm at V1 and 45.7 ± 29 mm at V4 (t-tests: p < 0.0001). From V0 to V4, improvements were also seen for pain at the other joints, neuropathic pain, functional independence, proprioception/balance, and the incidence of sprains and dislocations/subluxations, although not all comparisons were statistically significant (p < 0.05 level). These results indicate that CGs may effectively reduce the pain and joint instability in non-vascular EDS patients. Full article

This study assessed differences in the oral health-related quality of life (OHRQoL) between subtypes of Ehlers-Danlos syndrome (EDS). For statistical analysis, participants were divided according to their subtype: classical EDS (cEDS), hypermobile EDS (hEDS), and vascular EDS (vEDS). All other subtypes were descriptively analyzed. Free-text questions and the German short form of the Oral Health Impact Profile (OHIP-14) were used. Finally, 295 questionnaires were included, representing 10 different EDS subtypes. The mean OHIP score of all participants was 19.6 points (standard derivation (SD) ± 12.3). The most predominant subtypes showed similar reduced OHRQoL, with 18.0 (cEDS, ±12.9), 19.5 (hEDS, ±12.0), and 15.2 (vEDS, ±11.6) OHIP points. For all other subtypes, the OHIP values varied. Participants waited an average of 21.8 years (±12.8) for their diagnosis. However, within the predominant subtypes, vEDS patients waited a noticeably shorter period of 13.3 years (±13.0; p = 0.004) compared to participants with hEDS. Additionally, this study showed no difference in OHRQoL for the predominant subtypes regardless of whether a participant was a self-help group member (18.8, ±12.0) or not (19.4, ±12.1; p = 0.327). Full article

In 2018, a new clinical subtype, caused by biallelic variants in the AEBP1 gene, encoding the ACLP protein, was added to the current nosological classification of the Ehlers–Danlos Syndromes (EDS). This new phenotype, provisionally termed EDS classical-like type 2 (clEDS2), has not yet been fully characterized, as only nine cases have been reported to date. Here we describe a patient, homozygous for a novel AEBP1 pathogenic variant (NM_001129.5 c.2123_2124delTG (p.Val708AlafsTer5)), whose phenotype is reminiscent of classical EDS but also includes previously unreported multiple congenital malformations. Furthermore, we briefly summarize the current principal clinical manifestations of clEDS2 and the molecular evidence surrounding the role of AEBP1 in the context of extracellular matrix homeostasis and connective tissue development. Although a different coexisting etiology for the multiple congenital malformations of our patient cannot be formally excluded, the emerging role of ACLP in TGF-β and WNT pathways may explain their occurrence and the phenotypical variability of clEDS2. Full article

The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular matrix and cell signaling. Although DS classically exerts physiological functions via interaction with collagens, growth factors, and heparin cofactor-II, new functions have been revealed through analyses of human genetic disorders as well as of knockout mice with loss of DS-synthesizing enzymes. Mutations in human genes encoding the epimerase and sulfotransferase responsible for the biosynthesis of DS chains cause connective tissue disorders including spondylodysplastic type Ehlers–Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. DS-deficient mice show perinatal lethality, skin fragility, vascular abnormalities, thoracic kyphosis, myopathy-related phenotypes, acceleration of nerve regeneration, and impairments in self-renewal and proliferation of neural stem cells. These findings suggest that DS is essential for tissue development in addition to the assembly of collagen fibrils in the skin, and that DS-deficient knockout mice can be utilized as models of human genetic disorders that involve impairment of DS biosynthesis. This review highlights a novel role of DS in tissue development studies from the past decade. Full article

21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3′untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30 kb deletion producing a chimeric TNXA/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers–Danlos syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population. Full article

Ehlers-Danlos syndrome (EDS) is a group of heterogeneous, rare diseases affecting the connective tissues. The main clinical signs of EDS are skin hyperextensibility, joint hypermobility, and skin fragility. Currently, the classification of EDS in humans distinguishes 13 clinical subtypes associated with variants in 20 different genes, reflecting the heterogeneity of this set of diseases. At present, variants in three of these genes have also been identified in dogs affected by EDS. The purpose of this study was to characterize the clinical and histopathological phenotype of an EDS-affected Chihuahua and to identify the causative genetic variant for the disease. The clinical examination suggested a diagnosis of classical EDS. Skin histopathology revealed an abnormally thin dermis, which is compatible with classical EDS. Whole-genome sequencing identified a heterozygous de novo 27 bp deletion in the COL5A2 gene, COL5A2:c.3388_3414del. The in-frame deletion is predicted to remove 9 amino acids in the triple-helical region of COL5A2. The molecular analysis and identification of a likely pathogenic variant in COL5A2 confirmed the subtype as a form of classical EDS. This is the first report of a COL5A2-related EDS in a dog. Full article

We investigated four cats with similar clinical skin-related signs strongly suggestive of Ehlers-Danlos syndrome (EDS). Cases no. 1 and 4 were unrelated and the remaining two cases, no. 2 and 3, were reportedly siblings. Histopathological changes were characterized by severely altered dermal collagen fibers. Transmission electron microscopy in one case demonstrated abnormalities in the collagen fibril organization and structure. The genomes of the two unrelated affected cats and one of the affected siblings were sequenced and individually compared to 54 feline control genomes. We searched for private protein changing variants in known human EDS candidate genes and identified three independent heterozygous COL5A1 variants. COL5A1 is a well-characterized candidate gene for classical EDS. It encodes the proα1 chain of type V collagen, which is needed for correct collagen fibril formation and the integrity of the skin. The identified variants in COL5A1 are c.112_118+15del or r.spl?, c.3514A>T or p.(Lys1172*), and c.3066del or p.(Gly1023Valfs*50) for cases no. 1, 2&3, and 4, respectively. They presumably all lead to nonsense-mediated mRNA decay, which results in haploinsufficiency of COL5A1 and causes the alterations of the connective tissue. The whole genome sequencing approach used in this study enables a refinement of the diagnosis for the affected cats as classical EDS. It further illustrates the potential of such experiments as a precision medicine approach in animals with inherited diseases. Full article

Background: Ehlers-Danlos syndrome (EDS) is a common non-inflammatory, congenital connective tissue disorder. Classical type (cEDS) EDS is one of the more common forms, typically caused by mutations in the COL5A1 and COL5A2 genes, though causative mutations in the COL1A1 gene have also been described. Material and methods: The study group included 59 patients of Polish origin, diagnosed with cEDS. The analysis was performed on genomic DNA (gDNA) with NGS technology, using an Illumina sequencer. Thirty-five genes related to connective tissue were investigated. The pathogenicity of the detected variants was assessed by VarSome. Results: The NGS of 35 genes revealed variants within the COL5A1, COL5A2, COL1A1, and COL1A2 genes for 30 of the 59 patients investigated. Our panel detected no sequence variations for the remaining 29 patients. Discussion: Next-generation sequencing, with an appropriate multigene panel, showed great potential to assist in the diagnosis of EDS and other connective tissue disorders. Our data also show that not all causative genes giving rise to cEDS have been elucidated yet. Full article

(1) Background: Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by joint hypermobility and skin hyperextensibility with atrophic scarring. Many cEDS individuals carry variants in either the COL5A1 or COL5A2 genes. Mosaicism is relatively common in heritable connective tissue disorders but is rare in EDS. In cEDS, a single example of presumed gonosomal mosaicism for a COL5A1 variant has been published to date. (2) Methods: An 8-year-old girl with cEDS was analyzed by next-generation sequencing (NGS). Segregation was performed by Sanger sequencing in her unaffected parents. In the father, the mosaicism of the variant was further analyzed by targeted NGS and droplet digital PCR (ddPCR) in the blood and by Sanger sequencing in other tissues. (3) Results: The NGS analysis revealed the novel germline heterozygous COL5A1 c.1369G>T, p.(Glu457*) variant in the proband. Sanger chromatogram of the father’s blood specimen suggested the presence of a low-level mosaicism for the COL5A1 variant, which was confirmed by NGS and estimated to be 4.8% by ddPCR. The mosaicism was also confirmed by Sanger sequencing in the father’s saliva, hair bulbs and nails. (4) Conclusions: We described the second case of cEDS caused by paternal gonosomal mosaicism in COL5A1. Parental mosaicism could be an issue in cEDS and, therefore, considered for appropriate genetic counseling. Full article

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS—classic and hypermobile—by trying to identify possible biomarkers that could be of great help to confirm patients’ diagnosis and their follow up. Full article

We report an extremely rare case of combined classical and periodontal Ehlers−Danlos syndrome (EDS) with early severe periodontitis and a generalized lack of attached gingiva. A German family with classical EDS was investigated by physical and dental evaluation and exome and Sanger sequencing. Due to the specific periodontal phenotype in the affected child, an additional diagnosis of periodontal EDS was suspected. Physical and genetic examination of two affected and three unaffected family members revealed a family diagnosis of classical EDS with a heterozygous mutation in COL5A1 (c.1502del; p.Pro501Leufs*57). Additional to the major clinical criteria for classical EDS—generalized joint hypermobility, hyperelastic skin, and atrophic scarring —the child aged four years presented with generalized alveolar bone loss up to 80%, early loss of two lower incisors, severe gingival recession, and generalized lack of attached gingiva. Due to these clinical findings, an additional diagnosis of periodontal EDS was suspected. Further genetic analysis revealed the novel missense mutation c.658T>G (p.Cys220Gly) in C1R in a heterozygous state. Early severe periodontitis in association with generalized lack of attached gingiva is pathognomonic for periodontal EDS and led to the right clinical and genetic diagnosis in the present case. Full article

Classical Ehlers–Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by variable degrees of skin hyperextensibility and fragility, atrophic scarring, and generalized joint hypermobility. The purpose of this study was to characterize the clinicopathological phenotype of a cEDS-affected Holstein calf and to identify the causative genetic variant associated with the disorder by whole-genome sequencing (WGS). A 3-day-old female Holstein calf was referred because of easily induced skin detachment and hyperextensibility in the neck. A complete clinical investigation was performed in the calf, dam, and maternal-grandmother. The calf and dam showed hyperextensibility of the neck skin and atrophic scarring; additionally, the calf presented skin fragility. Moreover, the histopathology of biopsies from the calf and its dam showed that the collagen bundles in affected skin areas were wavy, short, thin, and surrounded by edema and moderate to severe acute hemorrhages. Genetic analysis revealed a private heterozygous missense variant in COL5A2 (c.2366G>T; p.Gly789Val) that was present only in the calf and dam. This confirmed the diagnosis of cEDS and represents the first report of a causal variant for cEDS in cattle and the first COL5A2-related large animal model. Full article