Classical-like Ehlers-Danlos syndrome type 1 (clEDS1) is a very rare form of Ehlers-Danlos syndrome caused by tenascin-X deficiency, with only 56 individuals reported in medical literature. Tenascin-X is an extracellular matrix protein needed for collagen stability. Previous publications propose that individuals with clEDS1 might be at risk of gastrointestinal (GI) tract perforations and/or tracheal ruptures. The aim of this study was to characterize complications resulting from perforations of the GI tract and/or tracheal rupture in an international case series of individuals with clEDS1 due to disease-related tissue fragility. This case series includes individuals with confirmed clEDS1 and GI perforations and/or tracheal ruptures from participating centers. Researchers who previously reported such individuals were contacted for additional information. A retrospective assessment of clinical features was performed. Fifteen individuals were included. Ten had spontaneous GI perforations, 7 of whom had multiple GI perforations. Almost all had severe diverticulosis. Three individuals experienced iatrogenic tracheal ruptures. Severe GI complications, such as perforation, and tracheal rupture were observed in a substantial number of individuals with clEDS1. As these features seem significantly more common in clEDS1 than in the average population, we advise vigilance during intubation and GI endoscopic interventions of individuals with clEDS1. Routine referrals to clinical geneticists are recommended for patients with symptoms indicative of clEDS1, especially with unexplained GI perforations and connective tissue symptoms. Our findings offer valuable insights for the clinical management of clEDS1 and underscore the importance of specialized care, providing a foundation for improved clinical guidelines and preventive strategies.

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. The clinical features of TNXB-related classical-like Ehlers-Danlos syndrome (clEDS) strongly resemble those seen in classic EDS (cEDS). Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising, but do not have atrophic scarring, as is seen in cEDS. There are also several other distinguishing clinical findings including anomalies of feet and hands, edema in the legs in the absence of cardiac failure, mild proximal and distal muscle weakness, and axonal polyneuropathy. Vaginal, uterine, and/or rectal prolapse can also occur. Tissue fragility with resulting rupture of the trachea, esophagus, and small and large bowel has been reported. Vascular fragility causing a major event occurs in a minority of individuals. Significant variability in the severity of musculoskeletal symptoms and their effect on day-to-day function between unrelated affected individuals as well as among affected individuals in the same family has been reported. Fatigue has been reported in more than half of affected individuals. The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound as a result of severe and painful foot deformities and fatigue. The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing. Treatment of manifestations: Non-weight-bearing exercise, physical therapy, and careful selection of analgesic medication to address joint pain; if pain is severe or debilitating, consider referral to a pain management specialist or clinic. The use of opioid medication should be avoided for chronic pain, as this does not lead to long-term pain relief and has the potential for addiction issues. Long-term chronic pain may result in the need for mental health services. Prompt assessment and management in a tertiary center is required for bowel rupture, arterial rupture, or organ rupture. Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the key characteristics of skin hyperextensibility and joint hypermobility. DDAVP® (deamino-delta-D-arginine vasopressin) may also be useful to normalize bleeding time in those with easy bruising. Standard treatment is applicable for joint dislocations, subjective muscle weakness, and cardiac abnormalities. Prevention of primary manifestations: Maintenance of a health body weight; low threshold for referral to gastroenterologist for evaluation of gastrointestinal symptoms; special attention during general anesthesia in order to provide adequate positioning and support as well as being aware of tissue fragility, which has been reported after intubation. Avoid invasive procedures unless absolutely medically necessary; consider carrying medical information or wearing jewelry denoting an increased risk of tissue fragility. Surveillance: Routine follow up ideally with rheumatologist, pain management clinic, and/or specialized EDS services, if available. Agents/circumstances to avoid: Sports with heavy joint strain, as well as contact sports; invasive procedures unless they are absolutely medically necessary; acetylsalicylate (aspirin) and long-term use of NSAIDS; use of opioid medication for chronic pain. Pregnancy management: It is important that the obstetrician and midwives are made aware of the diagnosis of clEDS during a pregnancy. Reported pregnancy and postpartum issues in affected women include miscarriage, premature rupture of membranes, post- or peripartum hemorrhage, and prolapse of the rectum, vagina, and/or uterus. Specialist delivery is strongly advised in view of reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe. TNXB-related clED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TNXB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the TNXB pathogenic variants have been identified in an affected family member, carrier testing and prenatal/preimplantation genetic testing are theoretically possible.