What You Should Know About Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (EDS) refers to a heterogeneous group of heritable disorders of connective tissue resulting in tissue fragility, skin hyperextensibility, and joint hypermobility. The true prevalence is unknown but is estimated at 1 in 5000.

When to Suspect EDS

Patients with hypermobile EDS or classic EDS present with chronic pain, joint hypermobility, multiple joint dislocations, poor wound healing, and skin changes, whereas patients with vascular EDS often present with spontaneous organ rupture or dissection at a young age. Other common features include flat feet, pectus excavatum, and a high arched palate. Mitral valve prolapse is frequently mentioned as typical but probably occurs at the same rate as in the general population.

EDS Subtypes

The 2017 International Classification of the Ehlers-Danlos Syndromes, published by the International EDS Consortium, lists 13 subtypes, each with its own classification criteria. Genetic defects are identified for 12 of the 13 subtypes (hypermobile EDS being the exception), broadly affecting either collagen structure, collagen folding, or extracellular matrix. Skin distensibility or fragility and joint hypermobility are the main features, but the degree to which these traits are expressed varies among the different subtypes.

The three most common subtypes — hypermobile EDS, classic EDS, and vascular EDS — are all autosomal dominant (or, in the case of hypermobile EDS, where the genetic abnormality has not been identified, presumed autosomal dominant); in up to half of classic and vascular subtypes the mutation occurs de novo. Features of the 13 subtypes can overlap, so the diagnosis is best confirmed with genetic testing.

Hypermobile EDS accounts for 80%-90% of EDS. In the absence of a known genetic mutation, the 2017 International Classification suggests a stringent set of criteria, including joint hypermobility, skin issues, a positive family history, and chronic musculoskeletal pain. Joint hypermobility often results in joint dislocations affecting the shoulders, kneecaps, or temporomandibular joints. Skin changes are not quite as striking or common as in classic EDS. Comorbid conditions include irritable bowel syndrome and postural orthostatic tachycardia syndrome.

Classic EDS is estimated to have a prevalence of 1 in 20,000. More than 90% of patients with classic EDS have a mutation in one of the genes encoding type V collagen, which is commonly found in the dermoepidermal junction. Thus, the major criteria for classic EDS are skin hyperextensibility and atrophic scarring. Large and small joint hypermobility are typical but not universal. Vascular complications are rare, though aortic root dilation is often present.

Vascular EDS is the rarest of these three subtypes, with an estimated prevalence of 1 in 90,000. Patients with this type of EDS have a mutation in a gene encoding type III collagen, a structural component of blood vessels, the uterus, and the bowel. Patients can have arterial ruptures, uterine ruptures, and spontaneous colon perforations. Large joint hypermobility is not seen in this variant, and the skin is only mildly hyperextensible but is thin, making the venous pattern underneath readily visible. Unlike the hypermobile or classic types, vascular EDS can be catastrophic; median survival is only 51 years. The majority of patients will have experienced a major vascular event or organ rupture by age 40, including aortic, splenic, renal, or cerebrovascular arterial ruptures.

History and Physical Exam

When considering the diagnosis of EDS, relevant history includes:

Family history of joint hypermobility or vascular events at a young age
Frequent atraumatic joint dislocations
Recurrent abdominal hernias (inguinal, umbilical)
Skin issues: hyperextensibility, fragility, atrophic scarring, striae, piezogenic papules
Any history of vessel rupture or dissection, pneumothorax, or colonic perforation in the absence of diverticula
As part of the physical examination, the clinician should check the Beighton score and adjust according to age. From puberty until age 50, an abnormal Beighton score is 5 or greater; beyond age 50, a Beighton score of 4 or above may be considered abnormal.
The clinician should also measure skin distensibility. At the dorsum of the hand, greater than 1.5 cm of distensibility is abnormal. For the neck, elbows, and knees, greater than 3 cm is considered abnormal.

One of the defining characteristics of hypermobile EDS is that patients can have chronic widespread pain. Patients with classic EDS and vascular EDS also can have joint hypermobility, but widespread pain is not disease-defining. Widespread pain is also common among patients with non-EDS joint hypermobility. The pathogenesis of the pain is unclear; some unsubstantiated hypotheses include reliance on musculotendinous structures for stability in the hypermobile joint, or that the hypermobile joint may be more susceptible to repetitive use injuries. Pain amplification, akin to that seen in fibromyalgia, may play a role and may explain other functional issues such as chronic gastrointestinal distress.

EDS Management

There is no cure for EDS. The goals of treatment are symptom management and injury prevention. Whether or not the joint hypermobility is syndromic, physical therapy is generally considered the mainstay of treatment, but high-quality evidence is lacking. A handful of small randomized controlled trials have demonstrated that some physical therapy results in better outcomes compared with no intervention at all.

Psychosocial support is key to the management of the patient’s pain. The clinician should offer validation that the pain is legitimate even if poorly understood. Accompanying anxiety and depression can be managed with psychotherapy. Cognitive-behavioral therapy is an effective modality for the management of chronic pain in other contexts. Pharmacologic agents commonly used for chronic pain management, such as tricyclic antidepressants, gabapentinoids, and serotonin-norepinephrine reuptake inhibitors may reduce the degree of pain.

Patients with vascular EDS, which can be catastrophic, should be made aware of the symptoms of potential complications, including severe abdominal pain (indicating arterial or organ rupture), chest pain (pneumothorax), and vision loss (retinal detachment). A baseline echocardiogram for all EDS patients and magnetic resonance angiography or CT angiography for those with vascular EDS may be helpful, although there is no protocol for ongoing monitoring. Ophthalmic complications can occur in a variety of the EDS syndromes, so regular ophthalmology exams are recommended to check for retinal and scleral fragility.

Other Potential Causes of Joint Hypermobility and Arterial Rupture

Marfan syndrome is another autosomal dominant defect in connective tissue. The mutation is in the FBN1 gene, which makes fibrillin. As with patients with EDS, those with Marfan syndrome can have joint hypermobility and aortic root dilatation but can be distinguished by their disproportionately tall stature, lens dislocation, pectus carinatum, and absence of the typical EDS skin findings.

Stickler syndrome is an autosomal dominant defect of either type II or type XI collagen. While joint laxity is a feature, these patients have characteristic craniofacial features, such as a cleft palate and micrognathia, severe myopia, and hearing loss.

Loeys-Dietz syndrome is an autosomal dominant defect in genes that encode transforming growth factor beta receptors. The disease often presents as arterial ruptures or dissections in pediatric patients who also have other features, such as hypertelorism, cleft palate, and a bifid uvula.

Karmela Kim Chan, MD, is an assistant professor at Weill Cornell Medical College and an attending physician at Hospital for Special Surgery and Memorial Sloan Kettering Cancer Center in New York City. Before moving to New York City, she spent 7 years in private practice in Rhode Island and was a columnist for a monthly rheumatology publication, writing about the challenges of starting life as a full-fledged rheumatologist in a private practice.

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