Forgotten Diseases Research Foundation

Ehlers-Danlos Syndrome, Classic (types 1 & 2)


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 Gene Review article linked to at the right estimates that type 1 of EDS occurs in one birth per 20,000; figures for type 2 are not known.

Clinical information

Signs and symptoms

Classic EDS is one of the two most common forms of EDS (the other is the hypermobile form). Its most striking features are joint hypermobility and loose skin that bruises or tears easily and heals slowly. The skin over healed wounds may also stretch with time, creating scars that are wide and odd-looking. See photos on this page for examples of skin problems in classic EDS. Like EDS in general, classic EDS is more common in women than men (in our survey of ~300 published cases of classic EDS, 64% of patients were female).

The clinical features of classic EDS tend to overlap with other forms of EDS, although there are differences that help distinguish it from the other forms (see Differential Diagnosis, below). In general, the following features occur commonly in classic EDS:

    Signs and symptoms of classic EDS

  • Loose or stretchy skin
  • Joint hypermobility
  • Joint dislocations or subluxations
  • Joint and/or muscle pain and/or headaches
  • Smooth, velvety skin
  • Fragile skin that may scar abnormally
  • Slow wound healing
  • Easy bruising (bruising may even occur spontaneously)
  • Molluscoid pseudotumors or subcutaneous spheroids (see photos and discussion below)
  • Flat feet
  • Weakness
  • Fatigue or easy loss of energy
  • Cardiac problems in a minority of patients, including mitral valve problems and aortic root dilatation
  • Flat feet

Molluscoid pseudotumors (see photos below) are fleshy calcified lesions that form over scars at pressure points on the body (often the elbows and knees). Alternatively, subcutaneous spheroids are small calcified nodules that form under the skin. They can be felt through the skin and may be moved. They form from fat globules that lose their blood supply and become calcified. They are visible on x-rays or scans.

Some patients with the classic form of EDS have distinctive facial features. These features are not as obvious, common, or numerous as they are in patients with other forms of EDS, such as vascular EDS. In addition, facial features of classic EDS may also overlap with those of other forms. However, awareness of the constellation of facial features associated with each type may help with diagnosis. In classic EDS, they include the following:

    Facial features that may occur in classic EDS

  • Epicanthal folds on the eyes
  • Blue sclerae
  • Micrognathia (small jaw)
  • Retrognathia (receding lower jaw)
  • Highly arched palate
EDS type 1 and EDS type 2

The classic form of EDS comprises what were initially seen as two forms of EDS: type 1 (also called the gravis form), and type 2 (also called the mitis form; 5). The original description of these two EDS subtypes noted that type 1 was the more severe of the two (5). Type 2 cases may not be diagnosed due to the mildness of medical problems relative to other forms of EDS. These two forms of EDS are now known to be caused by mutations in the same gene. No genotype/phenotype correlations are known at this time.

The prevalance of EDS type 1 was once estimated at 1 person in 20,000 (6). This figure did not account for cases of EDS type 2. Thus, the figure of 1 person in 20,000 underestimates the prevalence of the classic form of EDS. Underestimation also occurs because milder forms of classic EDS may not be diagnosed.

Diagnosis and Testing

Classic EDS is an autosomal dominant disorder. This term means that it is usually passed from one affected parent to a child. However, it can also occur sporadically in a person without an affected parent. Each form appears to occur relatively half the time.

Mutations in one of two type 5 collagen genes can cause classic EDS; the genes are COL5A1 and COL5A2. In addition, mutations in COL5A1 appear to account for the majority of cases, and together, mutations in these two genes may account for up to 90% of all cases (7). In addition, mutations in the gene COL1A1 account for a small minority of cases of classic EDS; COL1A1-EDS may be more severe than EDS caused by the COL5A1 and 2 genes. Mutations in COL1A1 are associated with a number of other medical conditions, including the arthrochalasia type of EDS, osteogenesis imperfecta, and Caffey disease. In a small number of cases, none of these genes is mutated. Thus, it is possible that other genes will be associated with classic EDS in the future, as research is ongoing. Diagnosis at this time is either based on clinical features or on clinical features combined with molecular testing.

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.

Differential Diagnosis

Other forms of EDS. The differential diagnosis for EDS-Classic includes all the other types of EDS. All forms of EDS involve joint hypermobility, and most also feature very soft, lax skin, as well as a variety of internal problems that result from weak or loose connective tissue (e.g. hernias, spinal column deformities, flat feet). However, some forms of EDS are more severe than others.

Classic EDS may be distinguished from the rarer vascular and kyphoscoliotic types by genetic testing: the vascular form is caused by mutations in COL3A1, and the kyphoscoliotic form is caused by mutations in PLOD1. In addition, these conditions are generally (although not always) much more severe than the classic form. Patients with vascular EDS have a particular facial phenotype that is not shared by classic type patients,, and those with the kyphoscoliotic form tend to have severe spinal deformities. Note also that EDS-vascular patients are prone to spontaneous ruptures of large blood vessels that may be fatal. For this reason, clinicians may wish to use genetic testing to definitively rule out this form of EDS in any patient suspected of having EDS.

The hypermobile form of EDS (EDS-H) is a relatively mild form of EDS. As its name implies, joint hypermobility is the primary feature of this form of EDS. The skin in EDS-H patients is typically not as stretchy as it is in patients with the classic form, although exceptions apply. In addition, EDS-H patients are prone to hearing loss, which does not appear to be a feature generally associated with classic EDS. Atrophic scars also do not appear to be a general feature of the hypermobile form of EDS-H.

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.

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.

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.



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. Beighton P et al. (1969) Variants of the Ehlers-Danlos syndrome. Clinical, biochemical, haematological, and chromosomal features of 100 patients. Ann Rheum Dis 28(3):228-245. Full text on PubMed.
  6. 6. Byers PH (2001) Disorders of collagen biosynthesis and structure. In The Metabolic and Molecular Bases of Inherited Disease, 2nd ed. Scriver, Beaudet, Sly, Valle, eds. editors. Edinburgh, UK: Churchill Livingstone.
  7. 7. Ritelli M et al. (2013) Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis 8:58. doi: 10.1186/1750-1172-8-58. Full text on PubMed.
  8. 8. Bicca EB et al. (2011) Classical Ehlers-Danlos syndrome: clinical, Histological and ultrastructural aspects. An Bras Dermatol 86(4 Suppl 1):S164-167. Full text from Scielo.

Above: Detail of an atrophic scar in a classic EDS patient. Source: reference 8.










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Above: Molluscoid pseudotumors (MPs) in classic EDS. MPs are fleshy calcified lesions that tend to form over
pressure points (elbows, knees). Photo: reference 7.



Above: Different scar types in people with EDS. From left to right: small atrophic scars, atrophic and hypertrophic scars
hypertrophic scars, and haemosiderotic scars. See reference 7.



Below: Scarring and bruising on two people with EDS. Bruises tend to appear on exposed areas of the skin, and
they may even appear spontaneously. The skin is also very fragile, and events that result in minor or no trauma to
an unaffected individual may cause a significant injury in an EDS patient. We even found a report of a boy who
suffered a gash on his shin after it came into contact with a cushion (Beighton69). Photos: reference 7.



Below: Skin hyperextensibility in classic EDS. In EDS, the skin is hyperextensible and also elastic. This term means
that skin snaps back into position after being extended. This fact can help distinguish EDS from conditions such as
cutis laxa, in which the skin is inelastic, and tends to sag. Photos: reference 7.



Page last modified on 2 October 2017.