Ehlers-Danlos syndrome (EDS) is an assorted group of inherited connective tissue disorders.  It is a result of impaired formation and integrity of connective tissue proteins, especially collagen.  Collagen is an abundant protein that functions as a glue binding cells together.  Since collagen is so prevalent within most of the body, there is common involvement of structures such as skin, joints, blood vessels, eyes, etc. in patients with EDS1. This disease is named in honor of Edvard Ehlers and Henri-Alexandre Danlos, physicians whose work helped to understand unusual symptoms of EDS.

Diagnosis / Clinical symptoms:

EDS individuals may have one or more of the following symptoms/conditions

Hyperextensibility of the joints: Extended, flexible joints, circus-like contortions, vulnerability to sprains, and spontaneous dislocations of joints1.

Hyperextensibility of the skin: Hyperextensibility of the skin, gaping wounds even in relatively minor trauma, poor wound healing and the development of severe scar tissue with excessive pigmentation known as keloids2.

Vascular changes: Arteries lose tensile strength leading to aneurysms (ballooning of the blood vessels)1. These ballooned segments are weakened and prone to distension and rupturing.

 Pulmonary alterations: The development of thick, sticky mucus secretions within the lung tissue (cystic lung disease), fluid accumulation and weakening of the lung adherence to the chest wall (subpleural blebs) and fluid-filled blisters at the top portions of the lungs (apical bullae), which can lead to collapse of the lung unrelated to pressure- or physical-induced trauma (spontaneous pneumothorax)3.

Dental abnormalities: Partial absence of the teeth (hypodontia), delayed eruption of permanent teeth, and malformation of the dentin (the chief material of the tooth which is harder and denser than bone that surrounds the pulp)1.

Besides physical examination, echocardiography is a particularly useful tool in diagnosing and monitoring patients with vascular type of EDS.  The most common abnormality noted via this imaging study is dilatation of the aortic root, termed annuloaortic ectasia4. Other congenital cardiac anomalies associated with EDS include atrial and ventricular septal defects, coarctation of the aorta (formation of a shelf-like blockage within the descending thoracic aorta), bicuspid aortic valve (vice the normal three leaflet valve), and complex conditions such as Tetralogy of Fallot (the most common cyanotic heart lesion comprised of four cardiac anomalies:  narrowing of the pulmonic valve, a large hole between the two ventricles, thickening of the right ventricle, and misalignment of the aorta).

 Prevalence:

EDS is truly a rare disease, affecting just one in a million people worldwide5. There are rather subtle forms of each of this condition (see below), leading to missed diagnosis or misclassification1. Therefore, the incidence rates stated above may be skewed.  With so few cases to report, no gender or racial predilection has been observed.

 Pathophysiology:

There are three different mechanisms by which EDS traits are produced6. The first of these features is a deficiency of collagen-producing enzymes, such as lysyl-hydroxylase and procollagen peptidase. The second is the dominant-negative effects of mutant collagen α-chains6. The third is haploinsufficiency of COL5A1 gene that encodes the proalpha1(V) chain of type V collagen7. The term haploinsuffiency refers to the presence of a single functional copy of a particular gene within diploid organisms, with the other homologous allele (which is supposed to be a functioning duplicate) inactivated.

 Classification:

Villefranche classification simplified EDS phenotypes from earlier 11 types to six8. This system grouped many forms of EDS that have similar symptoms, and thus reduced the complexity in diagnosis. These six variants are detailed in Table 1.

Table 1:  The Villefranche Classification of EDS

 One that is not incorporated into this schema is known as the occipital horn syndrome.  This particular form is a disorder of copper transport9. Copper is an integral cofactor for a number of biosynthetic pathways, one of which involves the formation of collagen.

 Regardless of the classification system used, there is considerable overlap with regards to patients and these variants, with more than one-third of patients exhibiting features of more than one form.  As one can see, most of the variants show some degree of joint hyperextensibility and skin fragility with poor wound healing and scarring.  More in depth descriptions on these variants can be found in the citations.

 Clinical Management:

There are not many treatment options available, yet the optimal management of EDS patients a series of lifestyle modifications is recommended, such as minimizing skin trauma brought about by trauma or excessive exposure to the sun, as well as a regular exercise regimen in order to strengthen muscles, which in turn decreases the risk of joint injury (such as the previously discussed spontaneous dislocations).  Patients with the vascular and ocular forms of EDS should avoid dangerous contact sports, such as martial arts and rugby9. There is even anecdotal mention that increases in intracranial pressure (within the brain) resulting from the Valsalva effect can be problematic, especially with the vascular and ocular forms; patients may be advised to refrain from such activities as playing brass musical instruments (trumpet, trombone), as well as activities that require frequent or constant squatting or bearing down.

The limited treatment choices available for EDS patients’ are unsatisfactory, with most care being supportive in nature.  Patients requiring surgical interventions should be treated with the utmost of caution due to enhanced problems of bleeding from spontaneous vascular rupture, scar formation, and potential compromises in airway maintenance.  Surgical re-excision of scars and keloids might provide for some cosmetic benefit, although this plastic surgery can also lead to problems as previously noted.

References and Further Readings:

1. Ceccolini, E, Schwartz, RA.  Ehlers-Danlos Syndrome.  www.emedicine.medscape.com, 2009.

2. Andreoli, TE, Carpenter, CCJ, Griggs, RC, Loscalzo, J.  Cecil’s Essentials of Medicine, 5th ed.  W.B. Saunders, 2001.

3. Chiu HT, Garcia CK. Familial spontaneous pneumothorax. Curr Opin Pulm Med. 2006;12:268-72

4. Otto, CM.  The Practice of Clinical Echocardiography, 3rd ed.  Saunders/Elsevier, 2007.

5. Mathew T, Sinha S, Taly AB, Arunodaya GR, Srikanth SG. Neurological manifestations of Ehlers-Danlos Syndrome. Neurol India. 2005;53:339-41.

6. Mao, JR, Bristow, J.  The Ehlers-Danlos Syndrome:  On Beyond Collagens.  The Journal of Clinical Investigation, 2001; 107:  1063-1069.

7. Wenstrup RJ, Florer JB, Willing MC, Giunta C, Steinmann B, Young F, Susic M, Cole WG. COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet. 2000;66:1766-76

8. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998; 77: 31–7.

9. Fitzpatrick, JE, Aeling, JL.  Dermatology Secrets, 2nd ed.  Hanley & Belfus, 2001.

Contributors: Sean Marcus Hancock, RDCS (AE), RCS, RCSA, RCIS

Staff Cardiovascular Technician and Clinical Educator

Naval Hospital Bremerton, Washington

and

Pochi R. Subbarayan PhD

University of Miami

March 2011