Ehlers-Danlos Syndrome Type Research Articles

Elucidating the roles of SOD3 correlated genes and reactive oxygen species in rare human diseases using a bioinformatic-ontology approach.

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10-7), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10-7), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10-9), EMILIN-1-related Connective Tissue Disease (p = 6.54x10-9), Holt-Oram Syndrome (p = 7.72x10-10), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10-15), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10-7), Congenital Glaucoma (p = 5.24x210-9), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10-16), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10-16), Retinoblastoma (p = 1.9x10-8), and Lynch Syndrome (p = 5.04x10-9). 35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.

Is Exon Skipping a Viable Therapeutic Approach for Vascular Ehlers-Danlos Syndrome with Mutations in COL3A1 Exon 10 or 15?

Vascular Ehlers-Danlos syndrome or Ehlers-Danlos syndrome type IV (vEDS) is a connective tissue disorder characterised by skin hyperextensibility, joint hypermobility and fatal vascular rupture caused by COL3A1 mutations that affect collagen III expression, homo-trimer assembly and secretion. Along with collagens I, II, V and XI, collagen III plays an important role in the extracellular matrix, particularly in the inner organs. To date, only symptomatic treatment for vEDS patients is available. Fibroblasts derived from vEDS patients carrying dominant negative and/or haploinsufficiency mutations in COL3A1 deposit reduced collagen III in the extracellular matrix. This study explored the potential of an antisense oligonucleotide (ASO)-mediated splice modulating strategy to bypass disease-causing COL3A1 mutations reported in the in-frame exons 10 and 15. Antisense oligonucleotides designed to redirect COL3A1 pre-mRNA processing and excise exons 10 or 15 were transfected into dermal fibroblasts derived from vEDS patients and a healthy control subject. Efficient exon 10 or 15 excision from the mature COL3A1 mRNA was achieved and intracellular collagen III expression was increased after treatment with ASOs; however, collagen III deposition into the extracellular matrix was reduced in patient cells. The region encoded by exon 10 includes a glycosylation site, and exon 15 encodes hydroxyproline and hydroxylysine-containing triplet repeats, predicted to be crucial for collagen III assembly. These results emphasize the importance of post-translational modification for collagen III homo-trimer assembly. In conclusion, while efficient skipping of target COL3A1 exons was achieved, the induced collagen III isoforms generated showed defects in extracellular matrix formation. While therapeutic ASO-mediated exon skipping is not indicated for the patients in this study, the observations are restricted to exons 10 and 15 and may not be applicable to other collagen III in-frame exons.

Postural Orthostatic Tachycardia Syndrome (POTS) as an Adverse Event to the Human Papilloma Virus (HPV) Vaccine and Its Relationship with Ehlers–Danlos Syndrome (EDS)

Gardasil 4, a human papilloma virus vaccine, has been shown to protect against various cancers, including cervical cancer. Common side effects include injection site pain, fever, headaches, and muscle aches. In some individuals, the severe side effect of postural orthostatic tachycardia syndrome (POTS) has been reported. POTS is characterized by the abnormal response of lightheadedness, blurry vision, and dizziness while transitioning to an upright posture. POTS predominately affects women, with more than eighty-five (85) percent of POTS patients being female. POTS, on average, takes five years and eleven months to receive diagnosis. Additionally, a strong association between POTS and Ehlers–Danlos Syndrome Type III (EDS) exists. Eighty (80) percent of patients with EDS have POTS. This severe side effect indicates that providers need to be aware of this strong association of HPV vaccinations and POTS. In this report, we will present a case of a young women with a past medical history significant for EDS type III who was diagnosed with POTS after receiving Gardasil 4 vaccination. This case demonstrates the need for physicians to be aware of the association of POTS with EDS type III and HPV vaccination. Physician awareness of the associations, signs, and symptoms of POTS and earlier testing at the first presentation of signs and symptoms will limit the negative impact on patient’s quality of life.

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.

Treatments related to temporomandibular disorders among patients with prevalent types of Ehlers-Danlos syndrome in Sweden

ABSTRACT 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.

Dysregulation of extracellular matrix and Lysyl Oxidase in Ehlers-Danlos syndrome type IV skin fibroblasts

BackgroundEhlers-Danlos syndrome Type IV (aka Vascular Ehlers Danlos, or vEDS) is a dominantly inherited mutation in the Collagen 3A1 gene (COL3A1). The disease is characterized by tissue friability and age-related susceptibility to arterial aneurysm, dissection and rupture as well as uterine and bowl tears. These clinical manifestations result in major surgical intervention and decreased life expectancy. Understanding how mutations in COL3A1 impact the structure and function of the extracellular matrix (ECM) is important to managing the disease and finding treatments.ResultsSkin fibroblasts from vEDS subjects heterozygous for the p.G588S pathogenic variant in the COL3A1 gene and a normal individual were cultured and studied. Proteomics analysis identified dozens of upregulated proteins related to extracellular matrix dysregulation that is characteristic of fibrosis. Gene expression libraries from cultured primary fibroblasts were screened for messenger RNA (mRNA) markers of ECM degradation. The proteomics and targeted gene expression array results were largely consistent with dysregulation of the extracellular matrix in vEDS. The data show upregulation of multiple Collagen proteins and genes, other ECM components, and enzymes related to ECM processing and turn-over. vEDS fibroblasts expressed significantly more cross linked C-Telopeptide of Collagen III (CTXIII) than normal fibroblasts, indicative of Collagen III degradation and turn-over. Further, the expression and activity of Lysyl Oxidase (LOX), an enzyme that initiates covalent cross-linking of soluble collagen and elastin into protease resistant fibers, is elevated in vEDS fibroblasts compared to normal fibroblasts.ConclusionTogether, these findings suggest dysregulated ECM deposition and processing, reminiscent of a state of fibrosis. Therapeutics that target the dysregulated ECM proteins or help replace damaged tissue may improve clinical outcomes.

Endovascular treatment of a ruptured aortic pseudoaneurysm and its complications in an 8-year-old child with Ehlers-Danlos syndrome type VI.

The procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) gene may affect arterial integrity through enzymatic roles and the modulation of vascular smooth muscle cells. We present a complicated vascular case of an 8-year-old male child with Ehlers-Danlos syndrome type VI. The patient was diagnosed with a ruptured pseudoaneurysm of the infrarenal abdominal aorta. Endovascular treatment was performed using a covered self-expandable endograft. However, complications arose at the vascular access sites during the procedure, highlighting arterial fragility. PLOD1 mutations can be associated with false abdominal aortic aneurysms or arterial fragility. Open repair poses a high risk for patients with Ehlers-Danlos syndrome. Although the long-term results are unknown, endovascular stent grafts may be a suitable option for emergency clinical scenarios such as ruptured abdominal aortic pseudoaneurysms.

Dermatosparaxis type of Ehlers-Danlos syndrome: case report

Background. The dermatosparaxial type of Ehlers-Danlos syndrome (EDSDERMS, VIIC, dEDS) is an extremely rare disorder. To date, 15 patients with this type of Ehlers-Danlos syndrome are known worldwide. The purpose was to improve knowledge and spread data about the orphan connective tissue di­sease — dEDS — on the example of a patient from a family in which the father and two sons have the same type of lesions. Materials and methods. We report a 6-year-old patient as well as his father and sibling with clinical symptoms of the dEDS, which we diagnosed based on the main diagnostic criteria: extreme skin fragi­lity, craniofacial features, superficial skin trauma, wrinkling of the palms, especially when they are exposed to water for a long time, and a tendency to ecchymosis with a risk of subcutaneous hematomas and bleeding. Secondary diagnostic criteria were represen­ted by atrophic scars, refractive errors (myopia), gingival margi­nal dysplasia, hypermobility of the finger and knee joints. The informed consent of the patient’s parents was obtained for the exa­mination and publication of information, and the parents agreed to the publication of clinical photographs. Results. After laboratory and instrumental studies and consultations with related specialists (hematologist, geneticist, cardiologist, pediatrician, orthopedist, dermatologist), we excluded such diseases as Marfan syndrome, MASS-phenotype, congenital coagulopathies and thrombocytopathies, hemophilia, isolated vascular pathologies, as well as other types of Ehlers-Danlos syndrome and identified dEDS in the patient only clinically. Genetic testing did not reveal any pathological mutations or exonic deletions/duplications. The negative result of genetic testing in dEDS is due to the fact that certain types of mutations (e.g., deep intronic mutations) cannot always be detec­ted by standard diagnostic genetic methods. Conclusions. It is possible to establish a diagnosis based on clinical symptoms, but an extended mutation search is mandatory for the entire family.

Hypermobility spectrum disorders and irritable bowel syndrome: A nationwide study of 1.6 million adolescents.

The association between hypermobility spectrum disorders/hypermobile type Ehlers-Danlos syndrome (HDS/hEDS) and irritable bowel syndrome (IBS) is yet to be clarified. We aimed to assess this association in a national sample of adolescents. A population-based cross-sectional study included 1627345 Israeli adolescents (58% male; mean age 17years) who were medically assessed before compulsory military service during 1998-2020. Diagnoses of HSD/hEDS and IBS were confirmed by board-certified specialists. The prevalence and odds ratios (ORs) for IBS in adolescents with and without HSD/hEDS were computed. A total of 4686 adolescents (2553 male) with HSD/hEDS were identified, of whom 71 were diagnosed with IBS (prevalence=1.5%). Of the 1621721 adolescents in the control group, 8751 were diagnosed with IBS (prevalence=0.5%). Unadjusted logistic regression revealed a significant association between HSD/hEDS and IBS (OR=2.16 [95% confidence interval, CI, 1.90-2.45]), which persisted in multivariable adjusted models (OR=2.58 [95% CI, 2.02-3.24]), and in several sensitivity analyses. The association was evident in both male and female adolescents with ORs of 2.60 (95% CI, 1.87-3.49), and 2.46 (95% CI, 1.66-3.49), respectively. The association was accentuated in a sensitivity analysis accounting for other medical and psychiatric comorbidities. We found a significant association between HSD/hEDS and IBS in both male and female adolescents. Clinical awareness of the association can promote early diagnosis of IBS and appropriate multidisciplinary treatment. Further research is required to identify the common pathological pathways of the conditions and to develop new IBS treatment strategies for people with HSD/hEDS.

Clinical characteristics of patients with hypermobile type Ehlers-Danlos syndrome (hEDS) and generalized hypermobility spectrum disorders (G-HSD): an online survey.

To examine the perspective of individuals with Hypermobile Ehlers-Danlos Syndrome (hEDS) and Generalized Hypermobility Spectrum Disorder (G-HSD), needed to help identify priorities and improve the lives of people living with these conditions. We conducted an online survey between November 2021 and January 2023. Participants were recruited through the Ehlers-Danlos Society's Research Surveys website. We obtained 483 responses and 396 were analyzed. 80% of the survey's respondents were individuals with hEDS, 90% were females, 30% were between 21 and 30, and 76% lived in North America, with 85% of the participants living in North America indicated being White or European American. Participants reported exercising from none to less than three times per week, with no physical therapy treatment. Ninety-eight percent of participants reported pain mainly at the neck (76%), lower (76%) and upper back (66%), knees (64%), shoulders (60%), and hips (60%). Approximately 80% of participants reported fatigue, joint hypermobility, joint instability, interference with daily activities, gastrointestinal problems, orthostatic hypotension, muscle weakness, and emotional distress. About 60% of respondents indicated walking issues, balance issues, and reduced joint proprioception. Nearly 40% of participants reported pelvic floor dysfunction and cardiovascular problems. Participants with hEDS and G-HSD reported pain on an average (SD) of 6.4 (± 1.3) and 5.9 (± 1.5) days in a typical week, respectively. People with hEDS and G-HSD desperately need more effective treatment options, a better diagnostic process, and education among health care providers.

Hypermobility spectrum disorders and active migraine in Israeli adolescents: A nationwide study.

To assess the association between hypermobility spectrum disorders/hypermobile type Ehlers Danlos Syndrome (HSD/hEDS) and migraine in a national sample of adolescents in Israel. The association between HSD/hEDS and migraine is unclear, even more so in pediatric populations. This population-based, cross-sectional study included 1,627,345 Israeli adolescents (945,519/1,626,407 [58%] males; mean age 17 ± 0.5 years) who were medically assessed before mandatory military service during 1998-2020. Diagnoses of migraine with at least one attack per month (active migraine) and HSD/hEDS were confirmed by certified specialists. The prevalences of active migraine in adolescents with and without HSD/hEDS were computed and the association between HSD/hEDS and active migraine was examined. Active migraine was significantly more prevalent in adolescents with HSD/hEDS (307/4686 [6.5%]) compared to those without HSD/hEDS (51,931/1,621,721 [3.2%]) (OR = 2.16, 95% CI 1.90-2.45). The association between HSD/hEDS and active migraine persisted in a multivariable analysis (OR = 2.08, 95% CI 1.85-2.34) and in several sensitivity analyses. We found a significant association between HSD/hEDS and active migraine in both male and female adolescents. Clinical awareness of the association can promote early diagnosis and treatment of migraine. Further research is required to identify appropriate pharmacologic and nonpharmacologic migraine treatment strategies for individuals with HSD/hEDS.

44 Detecting conformational differences in Fragile Foal Syndrome carriers utilizing artificial intelligence

Conformation traits impact gait and performance, and as a result vary based on intended use of the horse. For example, a horse with longer legs can cover a greater distance per stride than one with shorter legs. Limb length, therefore, is advantageous for horses expected to travel long distances for extended periods of time but may not be for those who go short distances at top speeds. Fragile Foal Syndrome (FFS) in horses results from a sequence change in PLOD1, the same gene that causes Ehlers Danlos Syndrome type IV (EDS-IV) in humans, a condition that results in longer limbs. Based on the phenotype observed in EDS, we hypothesize that FFS in the carrier state may impact extremity length including the neck, forelimbs, and hindlimbs in horses. To measure conformation parameters, we first digitally labeled specific anatomical points on a video recording of a trotting horse using the software package DeepLabCut (DLC). Representative frames for each horse at the same point within the stride were extracted from the video. The X, Y coordinates of each anatomical label were used to quantify conformation geometry. Frame extraction was done with a custom designed graphical interface that ensured the user could identify the ideal frame matching an identical body position across all horses examined. X,Y coordinate output files were thenanalyzed with a custom gait parameter pipeline written in MatLab to calculate the neck, forelimb, and hindlimb length. Each measurement was scaled to account for the varying distance horses were from the camera. Pulled tail hair was utilized to extract DNA and genotype each horse using PCR-RFLP, then followed by Sanger Sequencing for confirmation. Conformational measures were compared between genotype categories (wild type vs, carrier) in JMP Pro. Preliminary results showed that FFS carriers (n = 7) had significantly longer forelimb (P = 0.0344, t-test), hindlimb (P = 0.0258, t-test), and neck (P = 0.0013, t-test) lengths compared with wild type horses (n = 7). Future work will increase the overall sample size and number of frames captured per individual to increase statistical power and allow investigation of more conformation traits including static joint angles and back lengths. Improved understanding of conformational phenotypes that may result from the FFS carrier genotype will inform future studies of equine physiology and connective tissue disorders, leading to better decision making for breeding, sales and training, and preventing injury and loss of foals to this disease.

An exemplary model of genetic counselling for highly specialised services.

With genomic testing being increasingly integrated into every day clinical practice and a wide range of practitioners ordering genetic tests, it is important that the scope of the genetic counselling role continues to evolve alongside these changes. We present an exemplary role for genetic counsellors in a highly specialised service within England's National Health Service for people who have or are suspected to have rare genetic types of Ehlers Danlos syndrome. The service employs genetic counsellors and consultants from the fields of genetics and dermatology. The service also works closely with other specialists and related charities and patient organisations. The genetic counsellors in the service provide routine genetic counselling such as diagnostic and predictive testing, but their role also includes the writing of patient literature and emergency and well-being resources, delivering workshops and talks, and the development of qualitative and quantitative research on the patient experience. Data from such research has informed the development of patient self-advocacy and supportive resources, raised awareness amongst healthcare professionals and enhanced the standard of care and outcomes for patients. The service aims to be an example of innovation and accessibility and provides a model that can be potentially adopted by other highly specialised services of rare genetic diseases.

Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome.

Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-O-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.

Direct Inspection of Primary Aortic Cell Transcriptomes Identifies Candidate Causative Variants in Patients with Thoracic Aortic Aneurysm

Background: Thoracic aortic aneurysm (TAA) is an aortopathy that predisposes to life-threatening aortic dissection. Autosomal dominant disorders associated with TAA include Marfan syndrome (FBN1), Loeys-Dietz syndrome (TGFBR1/2, SMAD3, TGFB2), and vascular type Ehlers-Danlos syndrome (COL3A1). Our objective was to identify single nucleotide variants (SNVs) in these six genes within the transcriptomes of primary aortic cells acquired from patients with aortopathy.Methods: Primary aortic cell lines were cultured directly from the medial layer of surgically explanted aortic tissues in 63 unrelated aortopathy patients. RNA samples were extracted from aortic cells for mRNA sequencing. RNA reads aligning to the 6 selected TAA genes were directly inspected using Integrative Genomics Viewer (Broad Institute), and the identified SNVs were filtered for downstream analysis.Results: Study patients were predominantly male and of European ancestry with a mean age of 52±18 years. Thirty-three (52%) patients had a bicuspid aortic valve, and 10 (16%) had family history of TAA or dissection. A total of 3740 SNVs were identified in patient transcriptomes, and these occurred at 905 distinct genomic coordinates. There were 115 SNVs that were unique within the cohort, not located within a 3’-untranslated region, and had ≥20 aligned reads at the SNV’s position. Using the application Franklin (Genoox) to estimate clinical interpretation, 8 unique SNVs were classified as pathogenic (P) or likely pathogenic (LP). Five of these P/LP SNVs were associated with reduced allelic expression, and gene expression level was below the 20th percentile of study samples for 6 P/LP SNVs. Eighty-six unique SNVs were classified as variants of uncertain significance (VUSs). A total of 39 patients (62%) had at least one SNV classified as P/LP/VUS.
 Conclusion: Transcriptomic analysis of primary aortic cells identified candidate causative SNVs and their relative allelic expression. Further analyses will investigate additional TAA-associated genes and integrate transcriptional abnormalities with genetic variants.

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

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. The aim of this study was the evaluation of the MIA3 gene role in hEDS patients. 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. 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. 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.

РЕДКИЕ ТИПЫ СИНДРОМА ЭЛЕРСА–ДАНЛО В ПРАКТИКЕ ПЕДИАТРА

Clinical observations of patients with arthrochalasia and classical-like types of Ehlers-Danlos syndrome (EDS) caused by mutations in the COL1A2 and TNXB genes, respectively, are presented in the article. These genes are involved in the organization of the correct structure and function of collagen. The presence of common links of pathogenesis, apparently, determines the formation of common clinical signs identified in patients (hypermobility syndrome, increased skin extensibility, impaired posture, deformity of the lower extremities, flat feet, mitral valve prolapse) and similar complaints (increased fatigue during exercise, pain in the legs). The peculiarity of the clinical picture in a female patient with arthrochalasia type of EDS were repeated dislocations/subluxations of large and small joints; and in a female patient with a classical-like type of EDS were repeated nosebleeds and the occurrence of paraorbital hematoma. In both observed cases it was possible to determine the type of disease only after a molecular genetic study and a joint analysis of phenotypic and genetic data. Establishing the type of EDS is important for determining the tactics of further medical observation of the patient and medical genetic counseling.

LIVING WITH EHLERS-DANLOS SYNDROME: FOLLOWING A YOUNG BOY THROUGH HIS UPS AND DOWNS ON HIS JOURNEY INTO ADULTHOOD

LIVING WITH EHLERS-DANLOS SYNDROME: FOLLOWING A YOUNG BOY THROUGH HIS UPS AND DOWNS ON HIS JOURNEY INTO ADULTHOOD

Annular elastolytic giant cell granuloma in a patient with Ehlers–Danlos syndrome

The article presents a clinical case of annular elastolytic giant cell granuloma (AEGCG) in a young patient with a vascular type of EhlersDanlos syndrome. The first clinical manifestations of AEGCG appeared on the skin in the right subclavian area about two years ago. Subsequently, new rashes appeared on the skin of the upper and lower extremities up to four new foci per year. The patient underwent ambulatory therapy as a solution of calcium gluconate 10% 5.0 ml No 10 i/v in every other day; a solution of chloropyramine hydrochloride 1.0 ml No 10 i/m every other day; betamethasone + salicylic acid ointment applied to the affected areas of the skin 2 times a day for 2 weeks. The treatment was ineffective, the rashes did not regress. External therapy with tacrolimus was carried out next, 0.1% ointment 2 times a day in the form of applications for 24 weeks but also without effect. The patient by herself started to take a dietary supplement containing 400 mg of collagen in 1 tablet; 3 types of amino acids 20 mg; vitamins B2 1.1 mg; B6 1.5 mg; calcium pantothenate 5 mg 2 tablets a day during meals. A month after the start of the application, she noticed a slight paling of the rashes. At the moment, the patient is under follow up.

Cervical Artery Dissections: Etiopathogenesis and Management.

Cervical Artery Dissection (CeAD) is a frequent stroke etiology for patients younger than 50 years old. The most common immediate complications related to CeAD are headache and neck pain (65–95%), TIA/ischemic stroke (>50%), and partial Horner’s syndrome (25%). The prevailing hypothesis regarding the pathogenesis of sCeAD is that the underlying constitutional vessel wall weakness of patients with sCeAD is genetically determined and that environmental factors could act as triggers. The stroke prevention treatment of CeAD remains controversial, involving anticoagulation or antiplatelet therapy and potentially emergent stenting and/or thrombectomy or angioplasty for selected cases of carotid artery dissection with occlusion. The treatment of headache associated with CeAD depends on the headache phenotype and comorbidities. Radiographically, more than 75% of CeAD cases present with occlusion or non-occlusive stenosis. Many patients demonstrate partial and complete healing, more commonly in the carotid arteries. One-fifth of the patients develop dissecting pseudoaneurysm, but this is a benign clinical entity with an extremely low rupture and stroke recurrence risk. Good recovery is achieved in many CeAD cases, and mortality remains low. Family history of CeAD, connective tissue disorders like Ehlers-Danlos syndrome type IV, and fibromuscular dysplasia are risk factors for recurrent CeAD, which can occur in 3–9% of the cases. This review serves as a comprehensive, updated overview of CeAD, emphasizing etiopathogenesis and management.