Rare Form of EDS Increases Risk of Tissue Fragility in GI Tract, Study Says

Patients with classical-like Ehlers-Danlos syndrome (EDS) due to tenascin-X deficiency, a rare form of EDS, are at risk for tissue fragility especially in the gastrointestinal tract, a study has found.

The study, “Classical-like Ehlers–Danlos syndrome: a clinical description of 20 newly identified individuals with evidence of tissue fragility,” was published in the journal Genetics in Medicine.

EDS comprises a group of genetic disorders that affect the connective tissue, which provides support to structures such as joints, blood vessels, and skin. Thus far, 13 types of EDS have been identified, including a rare form of classical-like EDS previously known as tenascin X (TN-X) deficiency. This type of EDS is caused by mutations in the TNXB gene, resulting in a deficiency of the TN-X protein.

TN-X is an important protein that interacts with collagen and provides cells with biochemical and structural support.

While TN-X deficiency shares several features of classical EDS, it does not involve tissue shrinkage and scarring, and is inherited in an autosomal recessive way, meaning that mutations in both gene copies are required for the disease to manifest.

So far, 31 patients with classical-like EDS (clEDS) due to tenascin-X deficiency have been reported in the literature.

In the study, a team led by researchers at the National Ehlers Danlos Syndrome Service in the U.K. reported the genetic and clinical features of 20 additional subjects diagnosed with this rare form of EDS.

These patients were diagnosed between the ages of 3 and 68, and all reported that their symptoms had started in childhood.

Researchers evaluated skin biopsies of 10 patients using transmission electron microscopy, a high-resolution imaging technique, to analyze tissue composition.

Six out of 10 patients had a normal biopsy result, while abnormal findings were observed in other patients, namely reduced collagen in the inner layer of the skin and changes in elastic fibers.

Genetic analysis revealed that 16 patients carried likely pathogenic (disease-causing) mutations in the TNXB gene, including 11 mutations not previously reported.

Clinical features of this clEDS group included hyperextensible skin, easy bruising, joint hypermobility, and velvety/smooth skin. Three patients experienced severe gastrointestinal complications — small or large bowel ruptures and one esophageal rupture.

Other clinical observations included two separate occurrences of spontaneous compartment syndrome, when an increase in pressure results in functional impairment of the underlying nerve and muscles; significant bruising; and musculoskeletal symptoms, including painful bone deformities, joint dislocation, and fatigue.

Pregnancy complications, including five bleedings and five miscarriages, were reported in 19 pregnancies.

Overall, the findings suggest that patients with clEDS due to tenascin-X deficiency are predisposed to develop tissue fragility, particularly in the gastrointestinal tract.

The study “increases the number of reported cases from 31 to 51 and broadens the phenotype of this condition, especially with the observation of tissue fragility of the gastrointestinal tract,” the researchers wrote.

The team also emphasized the importance of counseling for patients about the risk of gastrointestinal complications and also urged caution when considering invasive gastrointestinal procedures.

Given the limited number of patients with this rare form of clEDS reported so far, “clinical and molecular confirmation of this diagnosis is essential,” the team added, noting that patients should undergo a close follow-up to better “understand the natural history [of the disease and] to develop better recommendations for management.”