Clinical and Molecular Characterization of a Novel Homozygous Frameshift Variant in AEBP1-Related Classical-like Ehlers Danlos Syndrome Type 2 with Comparison to Previously Reported Rare Cases.

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.

Impairment of lung volume perception and breathing control in hypermobile Ehlers-Danlos syndrome.

Breathing difficulties and exertional dyspnea are frequently reported in hypermobile Ehlers-Danlos syndrome (hEDS); however, they are not clearly explained. An impaired proprioception or the addition of a cognitive task could influence ventilatory control. How can the perception of lung volume be measured? Is lung volume perception impaired in hEDS patients? Is the breathing control impaired during a cognitive task in hEDS patients? A device was developed to assess the accuracy of lung volume perception in patients with hEDS and matched control subjects. In the second step, ventilation was recorded in both groups with and without a cognitive task. Two groups of 19 subjects were included. The accuracy of lung volume perception was significantly (P < 0.01) lower at 30% of inspired vital capacity in patients with hEDS in comparison to the control group, and they showed erratic ventilation (based on spatial and temporal criteria) when performing a cognitive task. These data support the influence of the proprioceptive deficit on ventilatory control in hEDS patients. These elements may help to understand the respiratory manifestations found in hEDS. Future research should focus on this relationship between lung volume perception and ventilation, and could contribute to our understanding of other pathologies or exercise physiology.Trial registration number: ClinicalTrials.gov, NCT05000151.

Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and mice.

Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2Cys896Arg KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.

Ehlers-Danlos syndromes: importance of defining the type.

Ehlers-Danlos syndromes (EDS) is an umbrella term describing 14 types, of which 13 are rare and monogenic, with overlapping features of joint hypermobility, skin, and vascular fragility, and generalised connective tissue friability. Hypermobile EDS currently has no identified genetic cause. Most of the rare monogenic EDS types can have neurological features, which are often part of major or minor diagnostic criteria for each type. This review aims to highlight the neurological features and other key characteristics of these EDS types. This should improve recognition of these features, enabling more timely consideration and confirmation or exclusion through genetic testing. In practice, many healthcare professionals still refer to patients as having 'EDS'. However, the different EDS types have distinct clinical features as well as different underlying genetic causes and pathogenic mechanisms, and each requires bespoke management and surveillance. Defining the EDS type is therefore crucial, as EDS is not in itself a diagnosis.

Development of a facile method to compute collagen network pathological anisotropy using AFM imaging.

Type I collagen, a fundamental extracellular matrix (ECM) component, is pivotal in maintaining tissue integrity and strength. It is also the most prevalent fibrous biopolymer within the ECM, ubiquitous in mammalian organisms. This structural protein provides essential mechanical stability and resilience to various tissues, including tendons, ligaments, skin, bone, and dentin. Collagen has been structurally investigated for several decades, and variation to its ultrastructure by histology has been associated with several pathological conditions. The current study addresses a critical challenge in the field of collagen research by providing a novel method for studying collagen fibril morphology at the nanoscale. It offers a computational approach to quantifying collagen properties, enabling a deeper understanding of how collagen type I can be affected by pathological conditions. The application of Fast Fourier Transform (FFT) coupled with Atomic Force Microscope (AFM) imaging distinguishes not only healthy and diseased skin but also holds potential for automated diagnosis of connective tissue disorders (CTDs), contributing to both clinical diagnostics and fundamental research in this area. Here we studied the changes in the structural parameters of collagen fibrils in Ehlers Danlos Syndrome (EDS). We have used skin extracted from genetically mutant mice that exhibit EDS phenotype as our model system (Col1a1Jrt/+ mice). The collagen fibrils were analyzed by AFM based descriptive-structural parameters, coupled with a 2D Fast Fourier Transform(2D-FFT) approach that automated the analysis of AFM images. In addition, each sample was characterized based on its FFT and power spectral density. Our qualitative data showed morphological differences in collagen fibril clarity (clearness of the collagen fibril edge with their neighbouring fibri), D-banding, orientation, and linearity. We have also demonstrated that FFT could be a new tool for distinguishing healthy from tissues with CTDs by measuring the disorganization of fibrils in the matrix. We have also employed FFT to reveal the orientations of the collagen fibrils, providing clinically relevant phenotypic information on their organization and anisotropy. The result of this study can be used to develop a new automated tool for better diagnosis of CTDs.

A narrative review of the literature on illness uncertainty in hypermobile ehlers-danlos syndrome: implications for research and clinical practice.

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by joint and skin laxity, and often accompanied by chronic pain, dysautonomia, increased distress and, functional limitations. The journey to accurate diagnosis is often prolonged due to unclear etiology of symptoms. This manuscript is a narrative review of the literature on illness uncertainty (IU) in hEDS, highlighting the unique facets of IU in this population, as compared to the broader chronic pain population (given symptom overlap between these two disease groups), that warrant additional investigation. Additionally, we considered the unique challenges associated with IU in the context of the developmental nuances of pediatric populations. Specifically, we aimed to (1) map the extant literature of the IU experience in chronic pain conditions broadly including the pediatric and adult research to identify key concepts related to IU and incorporate potential developmental considerations in IU; (2) delineate and describe the IU experience specifically in patients with hEDS, with the goal of identifying gaps in the literature based on aspects of presentation in hEDS that do and do not differ from the broader chronic pain population; and (3) elucidate the potential areas of adverse impact of IU in both general chronic pain populations, and those with hEDS specifically, to provide actionable areas for future research and clinical care of individuals with hEDS. Results of this review indicate that IU has been well-studied in chronic pain generally, but inadequately evaluated in hEDS specifically. Specific features of hEDS (complexity of the disorder, involvement of multiple bodily systems, contribution of organic pathology) may uniquely contribute to IU in this population. This review suggests that ambiguities surrounding the diagnosis of hEDS, symptom course, and treatment recommendations, along with misdiagnosis, perceived dismissal of symptoms, or attribution of symptoms to mental health concerns might increase risk for IU and related distress in patients. CONCLUSION: Findings from the present review suggest that distinct features of hEDS yield a set of driving factors for IU that may be somewhat different than those faced by patients with chronic pain or other medical conditions. The development of a validated measure of IU to appropriately assess this construct in patients with hEDS is a research priority. In the clinical setting, providers should be attentive to the potentially aversive diagnostic and treatment experiences reported by patients and attempt to provide clear explanations based on the extant knowledge of hEDS, and implement best-practice recommendations for multidisciplinary treatment.

Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders occurring in both human and veterinary patients. The genetics of these disorders are poorly described in small animal patients. HYPOTHESIS/OBJECTIVES: Define the clinical manifestations and genetic cause of a suspected form of EDS in a cat. ANIMALS: A 14-week-old male domestic medium hair cat was presented with skin hyperextensibility and fragility. The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia. METHODS: Blood samples and a skin biopsy sample were collected from the affected cat. Clinical examinations, histology, electron microscopy and whole genome sequencing were conducted to characterize the clinical presentation and identify possible pathogenic DNA variants to support a diagnosis. Criteria defining variant pathogenicity were examined including human disease variant databases. RESULTS: Histology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower-like collagen fibrils in cross-section. Whole genome sequencing and comparison with 413 cats in the 99 Lives Cat Genome Sequencing Consortium database identified a novel splice acceptor site variant at exon 4 in COL5A1 (c.501-2A>C). CONCLUSIONS AND CLINICAL IMPORTANCE: Our report broadens the current understanding of EDS in veterinary patients and supports the use of precision medicine techniques in clinical veterinary practice. The classification of variants for pathogenicity should be considered in companion animals.

Otological Features of Patients with Musculocontractural Ehlers-Danlos Syndrome Caused by Pathogenic Variants in CHST14 (mcEDS-CHST14).

Musculocontractural Ehlers-Danlos syndrome (EDS) caused by pathogenic variants in CHST14 (mcEDS-CHST14) is a subtype of EDS characterized by multisystem malformations and progressive fragility-related manifestations. A recent international collaborative study showed that 55% of mcEDS-CHST14 patients had hearing loss (HL), more commonly of the high-frequency type. Here, we report the first systemic investigation of the otological features of patients with this disorder based on the world's largest cohort at Shinshu University Hospital. Nine patients [18 ears; four male and five female patients; mean age, 18 years old (range, 10-28)] underwent comprehensive otological evaluation: audiogram, distortion product otoacoustic emission (DPOAE) test, and tympanometry. The audiogram, available in all 18 ears, showed HL in eight patients (8/9, 89%) and in 14 ears (14/18, 78%): bilateral in six patients (6/9, 67%) and unilateral in two (2/9, 22%); mild in eight ears (8/18, 44%) and moderate in six (6/18, 33%); and high-frequency HL in five (5/18, 28%) and low-frequency HL in five (5/18, 28%). An air-bone gap was detected in one ear (1/18, 6%). DPOAE was available in 13 ears, with the presence of a response in five (5/13, 38%) and the absence in eight (8/13, 62%), including in three ears of normal hearing. Tympanometry results were available in 12 ears: Ad type in nine (9/12, 75%) and As type in one (1/12, 8.3%). Patients with mcEDS-CHST14 had a high prevalence of HL, typically sensorineural and bilateral, with mild to moderate severity, of high-frequency or low-frequency type, and sometimes with no DPOAE response. The pathophysiology underlying HL might be complex, presumably related to alterations of the tectorial membrane and/or the basilar membrane of Corti associated with disorganized collagen fibril networks. Regular and careful check-ups of hearing using multiple modalities are recommended for mcEDS-CHST14 patients.

Identification of an ADAMTS2 frameshift variant in a cat family with Ehlers-Danlos syndrome.

We investigated 4 European domestic shorthair kittens with skin lesions consistent with the dermatosparaxis type of the Ehlers-Danlos syndrome, a connective tissue disorder. The kittens were sired by the same tomcat but were born by 3 different mothers. The kittens had easily torn skin resulting in nonhealing skin wounds. Both clinically and histologically, the skin showed thin epidermis in addition to inflammatory changes. Changes in collagen fibers were visible in electron micrographs. The complete genome of an affected kitten was sequenced. A one base pair duplication leading to a frameshift in the candidate gene ADAMTS2 was identified, p.(Ser235fs*3). All 4 affected cats carried the frameshift duplication in a homozygous state. Genotypes at this variant showed perfect cosegregation with the autosomal recessive Ehlers-Danlos syndrome phenotype in the available family. The mutant allele did not occur in 48 unrelated control cats. ADAMTS2 loss-of-function variants cause autosomal recessive forms of Ehlers-Danlos syndrome in humans, mice, dogs, cattle, and sheep. The available evidence from our investigation together with the functional knowledge on ADAMTS2 in other species allows to classify the identified ADAMTS2 variant as pathogenic and most likely causative variant for the observed Ehlers-Danlos syndrome.

COL1A1 and COL1A2 variants in Ehlers-Danlos syndrome phenotypes and COL1-related overlap disorder.

Pathogenic variants in COL1A1 and COL1A2 are involved in osteogenesis imperfecta (OI) and, rarely, Ehlers-Danlos syndrome (EDS) subtypes and OI-EDS overlap syndromes (OIEDS1 and OIEDS2, respectively). Here we describe a cohort of 34 individuals with likely pathogenic and pathogenic variants in COL1A1 and COL1A2, 15 of whom have potential OIEDS1 (n = 5) or OIEDS2 (n = 10). A predominant OI phenotype and COL1A1 frameshift variants are present in 4/5 cases with potential OIEDS1. On the other hand, 9/10 potential OIEDS2 cases have a predominant EDS phenotype, including four with an initial diagnosis of hypermobile EDS (hEDS). An additional case with a predominant EDS phenotype had a COL1A1 arginine-to-cysteine variant that was originally misclassified as a variant of uncertain significance despite this type of variant being associated with classical EDS with vascular fragility. Vascular/arterial fragility was observed in 4/15 individuals (including one individual with an original diagnosis of hEDS), which underscores the unique clinical surveillance and management needs in these patients. In comparison to previously described OIEDS1/2, we observed differentiating features that should be considered to refine currently proposed criteria for genetic testing in OIEDS, which will be beneficial for diagnosis and management. Additionally, these results highlight the importance of gene-specific knowledge for informed variant classification and point to a potential genetic resolution (COL1A2) for some cases of clinically diagnosed hEDS.

Degradation of collagen I by activated C1s in periodontal Ehlers-Danlos Syndrome.

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, lack of attached gingiva and thin and fragile gums leading to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex. Previously we showed that pEDS pathogenic variants trigger intracellular activation of C1r and/or C1s, leading to extracellular presence of activated C1s. However, the molecular link relating activated C1r and C1s proteases to the dysregulated connective tissue homeostasis in pEDS is unknown. Using cell- and molecular-biological assays, we identified activated C1s (aC1s) as an enzyme which degrades collagen I in cell culture and in in vitro assays. Matrix collagen turnover in cell culture was assessed using labelled hybridizing peptides, which revealed fast and comprehensive collagen protein remodeling in patient fibroblasts. Furthermore, collagen I was completely degraded by aC1s when assays were performed at 40°C, indicating that even moderate elevated temperature has a tremendous impact on collagen I integrity. This high turnover is expected to interfere with the formation of a stable ECM and result in tissues with loose compaction a hallmark of the EDS phenotype. Our results indicate that pathogenesis in pEDS is not solely mediated by activation of the complement cascade but by inadequate C1s-mediated degradation of matrix proteins, confirming pEDS as a primary connective tissue disorder.

Dermatologic manifestations and diagnostic assessments of the Ehlers-Danlos syndromes: A clinical review.

BACKGROUND: The Ehlers-Danlos syndromes (EDSs) comprise a group of connective tissue disorders that manifest with skin hyperextensibility, easy bruising, joint hypermobility and fragility of skin, soft tissues, and some organs. A correct assessment of cutaneous features along with the use of adjunct technologies can improve diagnostic accuracy. OBJECTIVES: To systematically review the cutaneous features and adjunct investigations of EDS. METHODS: A search of PubMed and Web of Science for EDS-related cutaneous features and additional investigations was undertaken from publication of the 2017 International Classification of EDS until January 15, 2022. RESULTS: One-hundred-and-forty studies involved 839 patients with EDS. The EDS female-to-male ratio was 1.36:1 (P < .001). A high prevalence of skin hyperextensibility, bruising, and soft skin were noted. Most patients with vascular Ehlers-Danlos syndrome showed venous visibility, skin fragility, and acrogeria. Classical EDS showed subcutaneous spheroids and molluscoid pseudotumours. In patients that underwent skin biopsies, only 30.3% and 71.4% showed features suggestive of EDS using light microscopy and transmission electron microscopy, respectively. LIMITATIONS: Retrospective study and small cases numbers for some EDS-subtypes. CONCLUSIONS: An accurate clinical diagnosis increases the chances of a molecular diagnosis, particularly for rarer EDS subtypes, whilst decreasing the need for genetic testing where there is a low clinical suspicion for a monogenic EDS-subtype.

Child abuse misdiagnosed as Ehlers-Danlos syndrome: A case report.

Child abuse is a sensitive subject, and its diagnosis is sometimes difficult and requires awareness among physicians of the conditions that can mimic its symptoms.We report the case of a child aged two years and eight months who, according to his mother, had suffered multiple traumas of accidental and spontaneous occurrence for which he was admitted several times to the Children's University Hospital Ibn Sina in Rabat.The diagnosis of Ehlers-Danlos syndrome was made following the first skin biopsy. During the last admission, the child presented with a bleeding wound that raised the nursing team's doubts; hence, they requested a medico-legal opinion. Our examination confirmed a diagnosis of physical abuse.

An exploratory study of clinical characteristics and gait features of adolescents with hypermobility disorders.

BACKGROUND: In adolescents with non-pathological and pathological joint hypermobility, gait deviations have been associated with pain and fatigue. It remains unclear what distinguishes the non-pathological form of joint hypermobility (JH) from pathological forms (i.e. hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD). Our objective was to identify discriminative clinical characteristics and biomechanical gait features between adolescents with hEDS/HSD, JH, and healthy controls (HC). METHODS: Thirty-two adolescents were classified into three subgroups (hEDS/HSD=12, JH=5, HC=15). Clinical characteristics (e.g. pain intensity and surface, fatigue, functional disability) were inventoried. The gait pattern was assessed using a three-dimensional, eight-camera VICON MX1.3 motion capture system, operating at a sample rate of 100 Hz (VICON, Oxford, UK). Spatiotemporal parameters, joint angles (sagittal plane), joint work, joint impulse, ground reaction force and gait variability expressed as percentage using Principal Component Analysis (PCA) were assessed and analysed using multivariate analysis. Multivariate analysis data is expressed in mean differences(MD), standard error(SE) and P-values. RESULTS: The hEDS/HSD-group had significantly higher fatigue score (+51.5 points, p = <0.001) and functional disability (+1.6, p < .001) than the HC-group. Pain intensity was significantly higher in the hEDS/HSD-group than the other subgroups (JH; +37 mm p = .004, HC; +38 mm, p = .001). The hEDS/HSD-group showed significantly more gait variability (JH; +7.2(2.0)% p = .003, HC; + 7.8(1.4)%, p = <0.001) and lower joint work (JH; -0.07(0.03)J/kg, p = .007, HC; - 0.06(0.03)J/kg, p = .013) than the other subgroups. The JH-group showed significantly increased ankle dorsiflexion during terminal stance (+5.0(1.5)degree, p = .001) compared to hEDS/HSD-group and knee flexion during loading response compared to HC-group (+5.7(1.8) degree, p = .011). SIGNIFICANCE: A distinctive difference in gait pattern between adolescents with non-pathological and pathological joint hypermobility is found in gait variability, rather than in the biomechanical features of gait. This suggests that a specific gait variability metric is more appropriate than biomechanical individual joint patterns for assessing gait in adolescents with hEDS/HSD.

A novel mutation in collagen transport protein, MIA3 gene, detected in a patient with clinical symptoms of Ehlers-Danlos hypermobile syndrome.

BACKGROUND: Collagen, the most abundant human protein, is a significant component of the extracellular matrix (ECM) in tissues and organs like skin, bone, ligaments, and tendons. Collagen secretion is a complex, multistage process involving many molecules. A protein playing one of the main functions in this process is TANGO1 encoded by MIA3 gene. In the hypermobile type of Ehlers-Danlos syndrome (hEDS), one of the most common collagenopathies with no known genetic background, disrupted secretion of many molecules (including collagen) was observed. OBJECTIVES: The aim of this study was the evaluation of the MIA3 gene role in hEDS patients. MATERIAL AND METHODS: One hundred patients with clinically diagnosed hEDS and negative next-generation sequencing (NGS) testing for connective tissue disorder (e.g. Ehlers-Danlos syndrome, osteogenesis imperfect (OI), Marfan syndrome, and others) were tested for molecular changes in the MIA3 gene. RESULTS: Among the 100 tested patients, 14 single structural changes in the MIA3 gene were detected. Thirteen were missense benign or likely benign, while 1 variant (c.567dup, p.Leu1880ThrfsTer6) was truncating the TANGO1 protein. CONCLUSIONS: We suppose that the presence of truncating variant (c.5637dup) in the MIA3 gene and disrupted secretion of connective tissue protein may be one of the pathogenic mechanisms of clinical symptoms present in the tested patient, but these findings require a more comprehensive multidimensional investigation.

Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes.

BACKGROUND AND PURPOSE: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood. STUDY PURPOSE: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes. METHODS: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire. RESULTS: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions. CONCLUSION: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.

Congenital Defects in a Patient Carrying a Novel Homozygous AEBP1 Variant: Further Expansion of the Phenotypic Spectrum of Ehlers-Danlos Syndrome Classical-like Type 2?

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-ß and WNT pathways may explain their occurrence and the phenotypical variability of clEDS2.

Clinical Presentation and Characteristics of the Upper Extremity in Patients with Musculocontractural Ehlers-Danlos Syndrome.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by defective dermatan sulfate biosynthesis, characterized by multiple malformations (craniofacial features, ocular and visceral malformations) and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Repeated dislocations and deformities of the joints due to joint relaxation are observed, causing serious damage to the musculoskeletal system of the whole body; however, the motor function of the upper limbs and the morphology of the bone joints have not been systematically investigated. In this study, we present a detailed and comprehensive report on upper limb lesions of 13 patients with a mean age at the first visit of 21 years. Twelve patients (92.3%) had a history of dislocation. Eleven patients (84.6%) had shoulder dislocations, and two patients (15.4%) had elbow dislocations. Four patients (30.8%) had elbow osteoarthritis, and three patients (23.1%) had distal radioulnar joint (DRUJ) osteoarthritis. The phalanges and metacarpals are thin, and the ratio of medullary cavity of the metacarpal bone decreases with age. As bone and joint deformity progresses, patients with mcEDS should be recommended to receive regular follow-up, including radiology. The present findings suggest an important role for dermatan sulfate in the maintenance of the skeletal system.

Alterations in glycosaminoglycan biosynthesis associated with the Ehlers-Danlos syndromes.

Proteoglycans consist of a core protein substituted with one or more glycosaminoglycan (GAG) chains and execute versatile functions during many physiological and pathological processes. The biosynthesis of GAG chains is a complex process that depends on the concerted action of a variety of enzymes. Central to the biosynthesis of heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS) GAG chains is the formation of a tetrasaccharide linker region followed by biosynthesis of HS or CS/DS-specific repeating disaccharide units, which then undergo modifications and epimerization. The importance of these biosynthetic enzymes is illustrated by several severe pleiotropic disorders that arise upon their deficiency. The Ehlers-Danlos syndromes (EDS) constitute a special group among these disorders. Although most EDS types are caused by defects in fibrillar types I, III, or V collagen, or their modifying enzymes, a few rare EDS types have recently been linked to defects in GAG biosynthesis. Spondylodysplastic EDS (spEDS) is caused by defective formation of the tetrasaccharide linker region, either due to ß4GalT7 or ß3GalT6 deficiency, whereas musculocontractural EDS (mcEDS) results from deficiency of D4ST1 or DS-epi1, impairing DS formation. This narrative review highlights the consequences of GAG deficiency in these specific EDS types, summarizes the associated phenotypic features and the molecular spectrum of reported pathogenic variants, and defines the current knowledge on the underlying pathophysiological mechanisms based on studies in patient-derived material, in vitro analyses, and animal models.

Spinal manifestations of Ehlers-Danlos syndrome: a scoping review.

OBJECTIVE: Since its initial description, the definition of Ehlers-Danlos syndrome (EDS) has notably changed. At present, it broadly refers to disorders of the connective tissue that are heritable and have similar features including joint hypermobility, dermal dysplasia, and vascular as well as internal organ fragility. There has been no comprehensive review of spinal manifestations of EDS in the recent literature. That has led to controversies in management protocols of this so-called orphan disease. METHODS: The authors used the latest version of the EDS classification from 2017, in which 13 subtypes were recognized. EDS has 19 different causal genes, mainly associated with collagen synthesis. Of these, 5 subtypes have associated spinal manifestations. RESULTS: Some of the spinal pathologies associated with EDS include Chiari malformation, craniocervical instability, kyphoscoliosis, segmental instability and kyphosis, spontaneous CSF leaks, Tarlov cyst syndrome, tethered cord, and problems associated with wound healing. Here, the authors briefly discuss the demographics, etiology, pathophysiology, clinical features, management strategies, and directions for further research for each of these manifestations. CONCLUSIONS: EDS belongs to the group of orphan diseases, with the total patient population being below 200,000. Further research on spinal manifestations of EDS is the need of the hour to establish clinical practice guidelines and close the significant knowledge gaps that currently exist.