Ehlers-Danlos Syndrome

 Ehlers-Danlos Syndrome

Written by Drew Gryczewski with Dr. Nabil Ebraheim

Ehlers-Danlos Syndrome (EDS) is a family of inherited connective tissue disorders that impacts collagen and manifests as a wide spectrum of symptoms ranging from joint hypermobility to severe vascular defects, such as arterial aneurysms and dissections. It currently is classified into thirteen subtypes. The defects in collagen can be separated into either a direct mutation in the genes encoding collagen or a mutation in the enzymes involved in the synthesis of collagen. Collagen is fibrillar structure that provides support and strength for the extracellular matrix and is found in essentially all the organs and tissues in the body (1). Collagen is synthesized from three subunits that follow the general form Glycine-X-Y where X is typically proline and Y is 4-hydroxyproline. Each individual chain is then used to form a triple helix which is the functional structure of collagen. The 4-hydroxyprolines are important for maintaining the triple helix. Most subtypes of Ehlers-Danlos Syndrome follow an autosomal dominant inheritance, however there are also subtypes that follow an autosomal recessive inheritance pattern (2). Ehlers-Danlos Syndrome is divided into 6 major subtypes (13 subtypes total) including: classic, hypermobile, vascular, kyphoscoliosis, arthrochalasia, and dermatosparaxis. The most common subtypes being the hypermobile and classical (3). Classic Ehlers-Danlos Syndrome (cEDS) is associated with a mutation in the COL5A1 and COL5A2 genes which encode type V collagen. Typical clinical finding with classic Ehlers-Danlos Syndrome include skin hyperextensibility, widened atrophic scars, and easy bruising. These signs are all major criteria for the diagnosis of classical Ehlers-Danlos syndrome. Molecular testing for a variant of type V collagen is helpful for making the diagnosis (1). 

One of the consequences experienced by individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) is recurrent joint dislocations and subluxations. The incidence of joint dislocation is closely related to the severity of the hypermobility of the joints. The ligamentous and capsular laxity have been attributed as the cause for dislocation and subsequent joint instability. The recurrence and burden of these frequent dislocations and subluxations tends to increase with age (1, 4). Joint dislocations occur in 75% of all cases of Ehlers-Danlos Syndrome with the most being seen in the hypermobile subtype with 95% reporting dislocations (5). Later in life, individuals who suffer from recurrent dislocations and sprains usually develop chronic pain that is difficult to treat (1). Vascular Ehlers-Danlos Syndrome (vEDS) is caused by a mutation in type III collagen specifically the COL3A1 gene. This type of collagen is commonly found in the walls of arteries and hollow organs. A defect in this collagen carries severe complications including aortic

aneurysms and dissections, intestinal perforations, spontaneous pneumothorax, and uterine rupture during pregnancy (6). A way that the vascular and classical Ehlers-Danlos Syndrome are

differentiated is by the associated skin manifestations. In classical Ehlers-Danlos, the skin is normally smooth and velvety and is hyperextensible. The vascular type of Ehlers-Danlos however, is not associated with hyperextensible skin but the skin is thinner and more transparent. This subtype has the worst prognosis due to the relative frequency of arterial rupture (1). 

Making the diagnosis of Ehlers-Danlos Syndrome in infants can be difficult as they present as a “floppy baby”, and this can be a sign of more devastating pathology (4). Treatment can include both conservative and surgical interventions, although surgery isn’t recommended unless it is absolutely required, due to the risk of surgery incision dehiscence, poor wound healing, and other increased risks. In conservative treatment, the goal is the stabilize the muscles and the joint. The glenohumeral joint which is frequently involved requires strengthening of the rotator cuff muscles to improve stability. This should be done along with strengthening the deltoids and scapular stabilizer muscles to further decrease scapular dyskinesia. A barrier in surgical treatment is the abnormalities in the connective tissue that is characteristic of Ehlers-Danlos Syndrome.

The goal of surgical intervention is to correct capsular laxity by augmentation of the ligaments and bony structures. While these procedures tend to yield satisfactory outcomes in the general

population, there has not been sufficient data collected on individuals with Ehlers-Danlos Syndrome and thus each plan of care should be individualized (5). Most people with Ehlers-Danlos Syndrome spend years searching for the diagnosis, due to lack of awareness and understanding throughout the healthcare system. It also can be difficult to recognize due to the wide range of comorbidities associated with it. Treatment typically requires treating individual symptoms by a team of different healthcare specialists.

References

1. De Paepe A, Malfait F. The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet. 2012 Feb 13;82(1):1-11. 

2. Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004 Jan;20(1):33-43. 

3. Scheufler O, Andresen JR, Andresen R. Surgical treatment of abdominal wall weakness and lumbar hernias in Ehlers-Danlos syndrome – Case report. International Journal of Surgery Case Reports. 2020 Sep 21;76:14-18. 

4. Beighton P, Horan F. Orthopaedic Aspects of Ehlers-Danlos Syndrome. J Bone Joint Surg. 1969 Aug 1;51 B(3):444-53

5. Broida SE, Sweeney AP, Gottschack MB, Wagner ER. JSES Reviews, Reports, and Techniques. 2021 Mar 23;1(3):155-64

6. Sage L, Russo ML, Byers PH, Demasi J, Morris SA, Puryear LN, Fulton DS, Shalhub S; Vascular Ehlers-Danlos Syndrome Research Collaborative. Setting a research agenda for vascular Ehlers-Danlos syndrome using a patient and stakeholder engagement model. J Vasc Surg. 2020 Oct;72(4):1436-1444