What is Ehlers-Danlos Syndrome?
Ehlers-Danlos Syndrome (EDS) is a heritable group of disorders affecting connective tissue. Connective tissue is the glue that holds our bodies together. Muscles, which allow us to move as we do, are tethered to our skeleton with tendons while the skeleton is held together by ligaments. Tendons and ligaments are both examples of connective tissues, and as you can imagine, disrupting the function of connective tissue has many consequences. While Ehlers-Danlos Syndrome is a heterogenous group of disorders, characteristic traits include joint laxity, hyperelasticity of the skin, and tissue fragility which can lead to lifelong and unpredictable pain (1) . The six subtypes of Ehlers-Danlos syndrome, Classical, Hypermobility, Vascular, Kyphoscholiosis, Artrochalasia, and Dermatosparaxis are each caused by mutations in genes that are responsible for the proper function of connective tissues (2). While prevalence varies by subtype, it is estimated that 1/5000 people suffer from Ehlers-Danlos Syndrome, many of whom are affected by Classical or Hypermobility subtypes (3).
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Of all of the types of EDS, Vascular Ehlers-Danlos Syndrome is considered to be the most rare and life threatening. Vascular EDS is associated with risk of arterial rupture and death at any age and is caused by mutations in the gene COL3A1 (4). Vascular EDS is inherited in a dominant pattern. Only 1 defective copy of the gene is needed to cause the condition, meaning that if one parent has a defective copy of COL3A1 there is a 50% chance that the child will be affected. It is estimated that vascular EDS effects 1 in every 90,000 people (7).
Type III collagen is found in skin, lungs, intestinal walls, and the walls of the blood vessels. (5) COL3A1 produces building blocks, called pro-alpha1 (III) chains, that make up Type III collagen. Three pro-alpha 1 (III) chains will combine to create type III procollagen which are rope-like, triple-stranded molecules. Type III procollagen must be processed by enzymes outside of the cell in order to arrange themselves into thin, long fibrils where each collagen molecule is cross linked to the other resulting in strong molecules that are able to support our cells (5). Disrupting the function of COL31A can have severe consequences .
Signs, Symptoms, and Diagnosis
Signs, Symptoms, and Diagnosis
Individuals affected with Vascular EDS have thin, translucent skin, characteristic facial features (shown right), easy bruising, and arterial, intestinal, and uterine fragility (4). The most common cause of death for individuals affected with Vascular EDS is arterial rupture. 50% occur in the chest and abdomen, 25% in the head and neck, and 25% in the extremities (6). Arterial rupture can be proceeded by an aneurysm, arteriovenous fistulae, or dissection, but can also be completely unexpected with no warning signs (4). For this reason, early identification of Vascular EDS can be a life saving intervention. Newborns may present with clubfoot or congenital dislocation of the hip. Childhood warning signs include inguinal hernias, pneumothorax, and recurring joint dislocations. (4) The major diagnostic criteria include: arterial rupture, intestinal rupture, uterine rupture during pregnancy, and a family history of Vascular EDS (4). Minor diagnostic criteria include the phenotypic characteristics listed above. Occurrence of two major diagnostic criteria is a strong indication of Vascular EDS and occurrence of two minor criteria warrants further investigation (4). In both cases, genetic testing can be done to confirm the diagnosis, as COL31A is the only gene known to cause Vascular EDS.
Treatment
25% of individuals affected by Vascular EDS have experienced significant medical problems by the age of 20, which goes up to 80% by the age of 40 (4). There is no cure for Ehlers-Danlos Syndrome. Management strategies for those affected by Vascular EDS include: avoidance of trauma, elective surgery, arteriograms, or routine colonoscopies, surveillance of the arterial tree to prevent rupture, and surgical intervention if bowel, arterial, or organ rupture occurs (4). In addition, special considerations should be made for individuals considering pregnancy as there is a 12% risk for death from peripartum arterial rupture or uterine rupture (4).
References:
1) Taj FT, Sajjan VV, Singh D. Ehlers-Danlos syndrome. Indian Dermatology Online Journal 2014;5(Suppl 1):S68-S70. doi:10.4103/2229-5178.144554.
2) Pauker, Susan P., and Joan Stoler. "Clinical Manifestations and Diagnosis of Ehlers-Danlos Syndromes." UpToDate. Ed. Peter H. Scher and Paul L. Romain. Wolters Kluwer, 12 Nov. 2014. Web. 20 Feb. 2015. <http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-ehlers-danlos-syndromes>.
3) "Ehlers-Danlos Syndrome." Genetics Home Reference. U.S. National Library of Medicine, 16 Feb. 2015. Web. 19 Feb. 2015. <http://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome>.
4) Pepin, Melanie G. "Ehlers-Danlos Syndrome Type IV." GeneReviews. University of Washington, Seattle, 3 May 2011. Web. 20 Feb. 2015. <http://www.ncbi.nlm.nih.gov/books/NBK1494/>.
5) "COL3A1 Gene." Genetics Home Reference. U.S. National Library of Medicine, May 2006. Web. 20 Feb. 2015. <http://ghr.nlm.nih.gov/gene/COL3A1>.
6) http://path.upmc.edu/cases/case504/dx.html
7) Pepin, Melanie G., Ulrike Schwarze, Kenneth M. Rice, Mingdong Liu, Dru Leistritz, and Peter H. Byers. "Survival Is Affected by Mutation Type and Molecular Mechanism in Vascular Ehlers–Danlos Syndrome (EDS Type IV)." Genetics in Medicine Print.
1) Taj FT, Sajjan VV, Singh D. Ehlers-Danlos syndrome. Indian Dermatology Online Journal 2014;5(Suppl 1):S68-S70. doi:10.4103/2229-5178.144554.
2) Pauker, Susan P., and Joan Stoler. "Clinical Manifestations and Diagnosis of Ehlers-Danlos Syndromes." UpToDate. Ed. Peter H. Scher and Paul L. Romain. Wolters Kluwer, 12 Nov. 2014. Web. 20 Feb. 2015. <http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-ehlers-danlos-syndromes>.
3) "Ehlers-Danlos Syndrome." Genetics Home Reference. U.S. National Library of Medicine, 16 Feb. 2015. Web. 19 Feb. 2015. <http://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome>.
4) Pepin, Melanie G. "Ehlers-Danlos Syndrome Type IV." GeneReviews. University of Washington, Seattle, 3 May 2011. Web. 20 Feb. 2015. <http://www.ncbi.nlm.nih.gov/books/NBK1494/>.
5) "COL3A1 Gene." Genetics Home Reference. U.S. National Library of Medicine, May 2006. Web. 20 Feb. 2015. <http://ghr.nlm.nih.gov/gene/COL3A1>.
6) http://path.upmc.edu/cases/case504/dx.html
7) Pepin, Melanie G., Ulrike Schwarze, Kenneth M. Rice, Mingdong Liu, Dru Leistritz, and Peter H. Byers. "Survival Is Affected by Mutation Type and Molecular Mechanism in Vascular Ehlers–Danlos Syndrome (EDS Type IV)." Genetics in Medicine Print.