OVERVIEW: What every practitioner needs to know

Are you sure your patient has Ehlers-Danlos syndrome? What are the typical findings for this disease?

Ehlers-Danlos syndrome is a group of inherited disorders of connective tissue that can affect joints, skin, blood vessels, muscles, ligaments, and visceral organs.

Classical EDS: Joint hypermobility, hyperextensible skin, poor wound healing with atrophic scarring, chronic pain, mild aortic dilation, autonomic dysfunction, osteopenia.

Hypermobile EDS: Joint hypermobility, chronic pain, mild aortic dilation, autonomic dysfunction.

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Vascular type of EDS: Joint hypermobility, aneurysms of the medium-sized vessels; rupture of hollow organs such as bowel and uterus.

Kyphoscoliotic type: Joint hypermobility, hypotonia, progressive kyphoscoliosis, scleral fragility, hyperextensible skin, fragile medium-sized arteries.

Arthrochalasia type: Joint hypermobility, short stature, midface hypoplasia, kyphosis, scoliosis, osteopenia, hyperextensible skin, poor wound healing.

Dermatosporaxis type: Joint hypermobility, marked skin fragility, redundant appearance of the skin. Also delayed closure of fontanels, edema of the eyelids, blue sclerae, short stature.

What other disease/condition shares some of these symptoms?

Joint laxity is a common manifestation of many hereditary disorders of connective tissue, and can be found as well in many skeletal dysplasias.

Typically, the aortic dilation of the classical and hypermobile types of EDS is mild and often resolves as the child attains adult body proportions.

Arterial aneurysms are also found in Marfan and Loeys-Dietz syndromes, but these most commonly involve the ascending thoracic aorta, whereas the vascular type of EDS typically involves the medium-sized arteries of the abdominal cavity, such as the hepatic, splenic and gastric arteries.

What caused this disease to develop at this time?

Ehlers-Danlos syndrome is a genetic disorder. Complications, including chronic pain, may arise secondary to trauma, such as an automobile accident or injury due to a fall.

Hypermobile joints are more susceptible to damage over time due to high-impact activities.

Vascular manifestations, including aneurysms of the medium-sized arteries in the vascular type of EDS, develop over time and may be exacerbated by systemic hypertension.

In the vascular type of EDS, rupture of hollow organs such as the uterus, may occur as a result of pregnancy; colonic rupture is more likely in the setting of severe constipation.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Classical and hypermobile types of EDS are diagnosed clinically. About half of patients diagnosed with the classical type will have mutations in one of the two genes encoding type V collagen, COL5A1 and COL5A2.

The vascular type of EDS is caused by mutations in the gene encoding type III collagen, COL3A1.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not useful in establishing the diagnosis of the classical and hypermobile types of EDS. If Chiari malformation, cranio-cervical of cervical instability are suspected, magnetic resonance (MR) imaging of the craniocervical junction and the neck in flexion and extension may be helpful.

MR angiography can be helpful in establishing the diagnosis of the vascular type of EDS.

If you are able to confirm that the patient has Ehlers-Danlos syndrome, what treatment should be initiated?

Parents are counseled to avoid high-impact exercise as this may exacerbate joint pain later in life. Lower-impact exercise such as walking, swimming, bicycling are encouraged.

There are multiple sources of chronic pain in EDS. Pain may be due to nerve impingement secondary to loose joints, muscle spasm or myofascial trigger points. Physical therapy to strengthen the muscles around lax joints can be helpful before the onset of severe pain. Once chronic pain has developed, treatment of muscle spasm and myofascial trigger points should be undertaken before toning and strengthening of the muscles is attempted. Topical analgesia through the use of lidoderm patches and diclofenac gel may avoid complications of systemic therapy.

Referral to pain management specialists may be necessary for patients with severe and/or refractory pain.

What are the adverse effects associated with each treatment option?

Treatment of chronic pain with narcotic medications may result in chronic constipation and dependency.

What are the possible outcomes of Ehlers-Danlos syndrome?

Many people with classical and hypermobile Ehlers-Danlos syndrome do not come to medical attention until a family member is diagnosed with the disorder. It is not uncommon for affected persons to remain asymptomatic well into the 5th and 6th decades. This seems to be particularly true of men, because of their increased muscle mass.

At the other end of the spectrum, however, are affected persons who become profoundly ill in their teens with postural orthostatic tachycardia syndrome (POTS) and other manifestations of autonomic dysfunction, sleep disturbances and chronic pain. These people suffer from severe disability as a result of their multiple symptoms. Neurologic complications may include Chiari malformation, cranio-cervical and cervical instability, as well as occult tethered cord leading to cauda equina syndrome.

Life expectancy is reduced in the vascular type of Ehlers-Danlos syndrome, due to aneurysms of the arterial tree (usually the medium sized arteries) and the risk of rupture of hollow organs such as colon and uterus.

What causes this disease and how frequent is it?

Ehlers-Danlos syndrome is a hereditary disorder of connective tissue.

The classical, hypermobile and vascular types of EDS are inherited in autosomal dominant manner. The arthrochalasia type may be dominant or recessive. The kyphoscoliotic and dermatosporaxis forms are inherited in an autosomal recessive pattern.

The classical type is caused by mutations in the type V collagen genes, COL5A1 and COL5A2 in approximately 50% of cases. The gene(s) causing the remaining cases of classical EDS have not yet been identified.

The gene(s) causing most cases of the hypermobile type have not yet been found. A small proportion of patients with the hypermobile type of EDS have mutations in the tenascin-X gene.

The vascular type of EDS is caused by mutations in COL3A1, which encodes type III collagen, the most prevalent collagen in the arterial wall.

The arthrochalsia type of EDS is caused by mutations in type I collagen (COL1A1 or COL1A2) affecting the N-propeptide cleavage site.

The dermatosporaxis type of EDS is caused by mutations in ADAMTS2, encoding procollagen-1-N-propeptidase.

How can Ehlers-Danos syndrome be prevented?

Ehlers-Danlos syndrome is a hereditary disorder. Severe musculoskeletal manifestations may be prevented by avoiding high-impact physical exercise. If a mutation in one of the two type V collagen genes or in type III collagen is identified, prenatal genetic diagnosis may be offered to expectant parents.

What is the evidence?

Beighton, P, Solomon, L, Soskolne, CL. “Articular mobility in an African population”. Annals of the Rheumatic Diseases. vol. 32. 1972. pp. 413-418. (Contains the original description of the "Beighton scale" for joint hypermobility.)

Beighton, P, DePaepe, A, Steinmann, B, Tsipouras, P, Wenstrup, RJ. “Ehlers-Danlos syndromes: revised nosology, Vellefranche, 1997”. Am J Med Genet. vol. 77. 1998. pp. 31-37. (This paper describes the "new" nosology for the various types of Ehlers-Danlos syndrome, as of 1997. At the time of this writing (2011), the nosology has not yet been revised since 1997.)

Levy, HP. “Ehlers-Danlos Syndrome, Hypermobility Type”. In at GeneTests: Medical Genetics Information Resource (database online). 1997-2011. (GeneReviews provide structured, updated, authoritative information about genetic disorders.)

Malfait, F, Wenstrup, RJ, De Paepe, A. “Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type”. Genet Med. vol. 12. 2010. pp. 597-605. (An excellent overview of the classical type of EDS.)

Milhorat, TH, Bolognese, PA, Nishikawa, M. “Syndrome of occipitoatlantoaxial hypermobility, cranial settling and Chiari malformation type I in patients with hereditary disorders of connective tissue”. J Neurosurg Spine. vol. 7. 2007. pp. 601-9. (Presentation of the clinical and radiographic presentation of cranio-cervical hypermobility, cranial settling and Chiari malformation in the hereditary connective tissue disorders, including EDS.)

“Online Mendelian Inheritance in Man, OMIM”. 2/8/11.

Pepin, M, Schwarze, U, Superti-Furga, A, Byers, PH. “Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type”. New Eng J Med. vol. 342. 2000. pp. 673-680. (An authoritative treatise on the vascular type of EDS.)

Pepin, MG, Byers, PH. “Ehlers-Danlos Syndrome, Type IV.”. In at GeneTests: Medical Genetics Information Resource (database online). 1997-2011. (GeneReviews provide structured, updated, authoritative information about genetic disorders.)

Rombaut, L, Malfait, F, Cools, A, De Paepe, A, Calders, P. “Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers-Danlos syndrome hypermobility type”. Disabil Rehabil. vol. 32. 2010. pp. 1339-1345. (An overview of the effects of hypermobile EDS on quality of life and pain.)

Yeowell, HN, Steinmann, B. “Ehlers-Danlos Syndrome, Kyphoscoliotic Form”. In at GeneTests: Medical Genetics Information Resource (database online). 1997-2011. (GeneReviews provide structured, updated, authoritative information about genetic disorders.)

Ongoing controversies regarding etiology, diagnosis, treatment

Neurosurgical complications, including Chiari malformation, craniocervical instability and cervical instability, as well as occult tethered cord, have only recently been associated with Ehlers-Danlos syndrome and are not widely recognized among neurologists, neurosurgeons, and pediatricians.