Forgotten Diseases Research Foundation

Ehlers-Danlos Syndrome, Hypermobility (type 3)


Ehlers-Danlos syndrome is a condition that affects connective tissue --- particularly, collagen. Collagen is an abundant structural protein found in muscles, tendons, skin and bones. It can be thought of as both holding the body together and strengthening it.

There are many subtypes of EDS. Although there are many differences between them, two clinical features occur in all forms of EDS. The first is joint hypermobility (often called loose or double joints). People with EDS can often move their joints in ways that are impossible for most unaffected people (see the photograph on this page). However, many people without EDS have loose joints, and having joint hypermobility does not mean that person has a medical disorder. The second clinical feature that occurs in every form of EDS is hyperextensible (stretchy) skin. In some forms (classic and kyphoscoliotic, for example), this feature is nearly universal. In our literature survey for our software tool, we found that stretchy skin occured in less than half of people with the hypermobile and vascular forms, more than half of patients with the periodontitis type, and in a large majority of people with the arthrochalasia type (>80%).

Joint laxity/hypermobility is usually assessed with a scoring system called the Beighton score, which was developed in the early 1970s (1). This simple system scores a person's ability to move a joint past certain angles. The highest score is 9 points, and higher scores mean greater joint laxity. Generally speaking, scores of 4 or higher (at any time, past or present) in persons under age 50 indicate joint hypermobility. Many EDS patients have scores of 8 or 9, although many have lower scores, and a minority do not have hypermobile joints. Interested readers may wish to see a basic description of the scale with photographs or a more technical description.

The joint laxity that is common in EDS puts patients at high risk for joint dislocations and subluxations. These problems can be painful, and in some cases, debilitating. Surgical procedures have been used to improve skeletal stability and improve quality of life; for examples and reviews, see references 2-4.

The EDS syndromes as a group also have a classification system. This sytem is called the Villefranche classification. Villefrance uses descriptive terms for different types of EDS (e.g. vascular, kyphoscoliotic). These terms are the formally accepted names for each type of EDS. Before the Villefanche classification, the different forms of EDS were numbered (type 1, type 2, etc). These numbers are still in common use today. As a result, we have included them here. Type 8 is officially referred to as the periodontitis type of EDS, but continues to be generally referred to as type VIII in the literature. We will use the numbered term here (though with the numeral 8).

The Villefranche system classifies the different forms of EDS based on clinical and, when possible, molecular criteria. Unfortunately, some forms of EDS have not yet been associated with mutations in any genes. In addition, different disorders can be caused by mutations in the same genes. The situation can be complex, but research aimed at fully understanding it is ongoing.

Tissue fragility is another common feature of EDS. This problem is very serious in the vascular type of EDS; patients with this form of EDS are at high risk for spontaneous ruptures of large blood vessels and bowel perforations. Surgery on a person with this type of EDS must be performed with great care as a result of this problem. People with the hypermobile form are also prone to blood vessel ruptures, they though tend to occur in the small blood vessels of these patients. Tissue fragility can also lead to hernias and problems in pregnancy. Fragile skin is also a common manifestation of EDS, especially in people with the classic, kyphoscoliotic, and periodontitis types.

EDS affects women more commonly than men. We decided to count the number of male and female patients while we were characterizing six different types of EDS for our diagnostic aid software. Altogether, we analyzed data from ~1,100 patients. Sex information was available for 1,075. The table below shows that although more EDS patients are women in each type of EDS, the female:male ratio varies between each type. For example, females dominated the individuals reported with the hypermobility type, while males comprised a substantial minority of kyphoscoliotic and arthrochalasia patients. The distribution was roughly even in EDS type 8. However, the low number of case reports for these three types of EDS may have affected the outcome of this small analysis.



Above: Percentages of male and female patients with different types of EDS. Source: V. Natale & FDRF.



According to NIH's Genetics Home Reference (see link at right), the prevalence of all forms of EDS is roughly 1 in 5,000 worldwide. The hypermobility type (EDS-H) is the most common form of EDS, and although exact figures are not known, the Gene Review article estimates that its prevalence is underestimated due to difficulites with diagnosis, and that it may occur in one person per 5,000 to 20,000.

Clinical information

Signs and symptoms

EDS-H is considered to be the mildest form of EDS. Its most striking features are joint hypermobility (see photo at the right) and joint pain (arthralgia). Pain may be out of proportion to what would be suggested by clinical findings. Additionally, EDS-H is more common in women than men. This fact may be related to sex-specific differences in the perception of pain and joint stability rather than an absence of disease in men per se (5). This uncertainty has not been fully resolved.

The skin in EDS-H patients is not as stretchy/hyperextensible as it is in patients with other forms of EDS. This fact may be helpful in diagnosis. In addition, piezogenic papules under the skin also occur in EDS-H. Piezogenic papules are fat-filled skin elevations that form when pressure is applied. They often occur in the feet. The photograph at the bottom of the page shows piezogenic papules that appeared in an EDS-H patient after compression was applied to her wrists.

There does not appear to be a distinctive facial appearance associated with EDS-H. The most common signs and symptoms of this condition are as follows:

    Signs and symptoms of EDS-Hypermobility

  • Joint hypermobility
  • Joint dislocations or subluxations (see photo below)
  • Joint and/or muscle pain and/or headaches
  • Mildly stretchy skin that appears normal after being released
  • Smooth, velvety skin
  • Fragile skin that may scar abnormally and/or easy bruising
  • Fragile blood vessels (especially capillaries) that are prone to rupturing
  • Poor balance and/or fear of falling
  • Clumsiness
  • Inability to stand for long periods
  • Flat feet
  • Trouble concentrating
  • Absent frenulum below the tongue (a tissue that anchors the tongue to the lower jaw)
  • Functional bowel disorders (e.g. irritable bowel syndrome)
EDS-H and benign joint hypermobility syndrome

A condition called joint hypermobility syndrome (JHS) is very similar to EDS-H, and many researchers consider them to be the same condition (6,7). This opinion is not shared universally, although sources such as Orphanet (see link at right) list JHS as being a synonym for the term EDS-hypermobility. This question will be answered definitively when one or more genes is associated with EDS-H.

Diagnosis and Testing

EDS-H is an autosomal dominant disorder. This term means that EDS-H is usually passed from one affected parent to a child. However, it can also occur sporadically in a family without an affected parent. Mutations in a gene called tenascin B (TNXB) cause EDS-H in a small number of cases (8,9). However, apart from this gene, researchers have not identified the gene or genes responsible for the vast majority of EDS-H cases. As a result, at this time, and the diagnosis is still clinical. The link at the right provides information about labs that test for mutations in TNXB.

It is important to remember that there is a lot of overlap between the different forms of EDS. This fact means that, in the absence of laboratory testing, accurate subcategorization of EDS in a patient may be difficult or even impossible. This fact is especially true of EDS-H, given the lack of genes associated with it.

Differential Diagnosis

Other forms of EDS. The differential diagnosis for EDS-H includes all the other forms of EDS. Mild forms of classic EDS (types 1 and 2) are most similar to EDS-H, and diagnoses of EDS-H are sometimes changed to EDS-Classic. Most EDS-classic patients have mutations in the genes COL5A1 or COL5A2, which encode type 5 collagen, although COL1A2 is mutated in a minority of cases. Together, the hypermobility and classic forms of EDS are estimated to make up ~80% of all EDS cases (10).

The vascular form of EDS (formerly called Sack-Barabas syndrome) deserves special consideration in this context. EDS-vascular patients are prone to ruptures of large blood vessels; these ruptures may be fatal. Because surgical management of any EDS patient is a possibility, clinicians may wish to rule out EDS-vascular in a person suspected of having EDS. All cases of EDS-vascular are caused by mutations in the gene COL3A1.

Overall, joint hypermobility occurs in a variety of medical conditions, and many people without a medical condition have lax joints. In fact, when not part of a disorder, hypermobile joints confer an advantage in sports such as gymnastics and ice skating, as well as in certain forms of dance.

Marfan syndrome. Most medical conditions involvong lax joints are relatively easy to distinguish from EDS, but some are not. Marfan syndrome is an example. Like EDS, Marfan syndrome is a connective tissue disorder and patients have lax joints. Marfan patients generally have a body type called a Marfanoid body habitus. This term means that a person is tall and slender, with long arms, hands, fingers, legs, feet and toes. A Marfanoid body habitus occurs in a minority of EDS-H patients, but it does not appear to be generally associated with classic EDS. The Marfan Foundation has many photographs of Marfan patients of different ethnicities. Unlike EDS patients, Marfan patients do not appear to have fragile skin and blood vessels.

Cutis laxa. Superficially, the stretchy skin found in most forms of EDS may be confused with cutis laxa type 1 and type 2, as stretchy skin is also a feature of these conditions. However, the skin in cutis laxa patients tends to sag and does not return to its normal position after being extended. Cutis Laxa patients often have a prematurely aged appearance.

Williams syndrome. The Gene Review on classic EDS (see link at right) has a list of other conditions that are part of the differential diagnosis for EDS. They include , which may be distinguished from classic EDS by specific intellectual disabilities, a specific personality type, and other factors. The list of conditions also includes Loeys-Dietz syndrome, Stickler syndrome, and a number of other conditions.



References

  1. 1. Beighton P et al. (1973) Articular mobility in an African population. Ann Rheum Dis 32(5):413-418. Full text on PubMed.
  2. 2. Cole AS et al. (2000) Recurrent instability of the elbow in the Ehlers-Danlos syndrome. A report of three cases and a new technique of surgical stabilisation. J Bone Joint Surg Br 82(5):702-704. Full text from publisher.
  3. 3. Weinberg J et al. (1999) Joint surgery in Ehlers-Danlos patients: results of a survey. Am J Orthop 28(7):406-409. Abstract on PubMed.
  4. 4. Shirley ED et al. (2012) Ehlers-Danlos syndrome in orthopaedics. Etiology, diagnosis, and treatment implications. Sports Health 4(5):394-403. Full text on PubMed.
  5. 5. Castori M et al. (2010) Ehlers-Danlos syndrome hypermobility type and the excess of affected females: possible mechanisms and perspectives. Am J Med Genet A 152A(9):2406-2408. Abstract on PubMed.
  6. 6. Tinkle BT et al. (2009) The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A 149A(11):2368-2370. Abstract on PubMed.     Full text from EDNF.
  7. 7. Castori M et al. (2012) Ehlers-Danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, aand systemic manifestations? ISRN Dermatology Volume 2012:Article 751768. doi: 10.5402/2012/751768. Full text on PubMed.
  8. 9. Schalkwijk J et al. (2001) A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 345:1167-1175. Full text from publisher.
  9. 9. Zweers MC et al. (2003) Haploinsufficiency of TNXB Is Associated with Hypermobility Type of Ehlers-Danlos Syndrome. Am J Hum Genet 73(1):214-217. Full text on PubMed.
  10. 10. Beighton P (1993) The Ehlers-Danlos syndromes. McKusick's Heritable Disorders of Connective Tissue (5th edition; ed. Peter Beighton); Mosby, St. Louis, Chapter 6; pages 216-217.









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Above: Joint hypermobility in the toe of an EDS patient.
See reference 1.


Above: Piezogenic papules that appeared in a female EDS patient
after pressing her wrists together. See reference 1 for details.
EDS patients often have these papules in their feet.



Below: Elbow hypermobility in EDS. Note the bruising on this patient's arm.
See reference 1.


Page last modified on 10 March 2017.