Ehlers Danlos Syndromes
What is EDS?
This is a brief summary of Ehlers-Danlos syndrome (EDS), and the different types that are described in the 2017 Classification of EDS (Malfait et al, 2017).
Ehlers-Danlos syndrome is a group of conditions that arise from genetic alterations in collagen. Collagens are proteins found throughout the body. There are a number of different types of collagen in the body, often found together in very particular combinations in different body tissues. We all make the same collagens, distributed throughout the body in the same way. The collagens give strength and support to, for example, skin, bone, blood vessels, the gut, and tissues in and around joints such as ligaments, tendons and cartilage.
The production of each type of collagen is genetically determined. Alterations to the genes that are responsible for either making collagen or allowing it to function properly can result in weaker or more fragile and stretchy tissues throughout the body. As a consequence of this certain physical findings and complications arise. It is the recognition of these patterns of physical signs and the identification of specific gene alterations that allow clinicians to separate out the different types of EDS.
There are several forms of EDS. The most common form of EDS is hEDS (you can see more information on it here), followed by the Classical (cEDS), then the Vascular type (vEDS).
All share common features, such as flexibility (hypermobile) and often instability (subluxation or dislocation) at the joints; abnormal skin (from mild papyraceous scars and stretchmarks in hEDS to severe atrophic scars in cEDS; and other fragile body tissues e.g., weak abdominal wall leading to hernias, stretchy blood vessels and varicose veins, and thin heart valves. However, some types have more severe physical signs than others, and some have unique characteristics too.
Apart from the Hypermobile type (for which there is no definitive genetic test at present), genetic abnormalities have been found in most types of EDS but may not be easily identifiable in every case.
The Types of EDS
There are several forms of EDS. Looking through the list of types might seem a little daunting, but for the majority of individuals the diagnosis is most likely to be the Hypermobile type (hEDS) (which we talk about separately, here), followed by the Classical (cEDS), then the Vascular type (vEDS).
All share common features, such as flexibility (hypermobile) and often instability (subluxation or dislocation) at the joints; abnormal skin (from mild papyraceous scars and stretchmarks in hEDS to severe atrophic scars in cEDS; and other fragile body tissues e.g., weak abdominal wall leading to hernias, stretchy blood vessels and varicose veins, and thin heart valves. However, some types have more severe physical signs than others, and some have unique characteristics too.
Apart from the Hypermobile type (for which there is no definitive genetic test at present), genetic abnormalities have been found in most types of EDS but may not be easily identifiable in every case.
Clinical EDS Subtype | Abbr. | Inheritance Pattern | Genetic basis | Protein |
|---|---|---|---|---|
1. Classical EDS | cEDS | AD | Major: COL5A1, COL5A1
Rare: COL1A1
c.934C>T, p.(Arg312Cys | Type V collagen
Type I collagen
|
2. Classical-like EDS | clEDS | AR | TNXB | Tenascin XB |
3. Cardiac-valvular | cvEDS | AR | COL1A2 (biallelic mutations that lead to COL1A2 NMD and absence of pro α2(I) collagen chains) | COL1A2 (biallelic mutations that lead to COL1A2 NMD and absence of pro α2(I) collagen chains) |
4. Vascular EDS | vEDS | AD | Major | Major: COL3A1
Rare: COL1A1
c.934C>T, p.(Arg312Cys)
c.1720C>T, p.(Arg574Cys)
c.3227C>T, p.(Arg1093Cys) |
5. Hypermobile EDS | hEDS | AD | Unknown | Unknown |
6. Arthrochalasia EDS | aEDS | AD | COL1A1, COL1A2 | Type I collagen |
7. Dermatosparaxis EDS | dEDS | dEDS | ADAMTS-2 | ADAMTS-2 |
8. Kyphoscoliotic EDS | kEDS | AR | PLOD1
FKBP14 | ZNF469
PRDM5 |
9. Brittle Cornea syndrome | BCS | AR | ZNF469
PRDM5 | ZNF469
PRDM5 |
10. Spondylodysplastic EDS | spEDS | AR | B4GALT7
B3GALT6
SLC39A13 | β4GalT7
β3GalT6
β3GalT6 |
11. Musculocontractural EDS | mcEDS | AR | CHST14
DSE | D4ST1
DSE |
12. Myopathic EDS | mEDS | AD or AR | COL12A1 | Type XII collagen |
13. Periodontal EDS | pEDS | AD | C1R
C1S | C1r
C1s |
Classical EDS
The diagnostic criteria for Classical EDS are primarily made up of skin and joint findings (Bowen et al, 2017). There may be a family history of the condition but this is not always the case. Typical features of cEDS are:
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Non-traumatic / spontaneous onset atrophic scars
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The skin is smooth and velvety to touch. It is also hyper-elastic – it is stretched easily but it snaps back in to shape when released unlike certain skin conditions like Cutis Laxa, a condition associated with abnormality of the protein Elastin. Other skin findings that may appear in Classical EDS include: raised and thickened layers of skin termed ‘molluscoid pseudotumours’; small mobile nodules deep in the skin called ‘subcutaneous spheroids’; herniations of underlying fatty tissue through the lower layer of the skin leading to small painful lumps called Piezogenic papules; blue, cold, and sweaty (but not painful) skin due to constriction of blood vessels that return to normal – called Acrocyanosis; and, Chilblains, red and painful swellings after exposure to cold.
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The skin is also very fragile. Its deep layers can split or shear following relatively minor trauma. Severe bruising then arises. Typical sites where this might occur include pressure points such as the elbows, buttocks, knees, and feet, and at sites commonly prone to blunt injury such as the scalp and forehead, and shins. Wound healing is delayed, and scars will often stretch to a considerable degree, and appear paper thin (papyraceous scars).
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Joint hypermobility in Classical EDS is typically widespread affecting both large and small joints. It is often noted first when a child starts to walk. Dislocations are common. Other complications of joint hypermobility such sprains and subluxations (partial dislocations) occur. Occasionally joints are painful but this seems far less common than in the Hypermobility type.
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There may be muscle weakness or low tone (hypotonia) perhaps manifesting in childhood as a delay in development of motor skills (e.g., holding head up, crawling, walking).
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Other tissues may be fragile: e.g., the diaphragm or abdominal wall leading to a hernia, or prolapse of the rectum (‘back passage’) from early childhood, or weakness of the pelvic floor and support structures of the womb during pregnancy.
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Occasionally (found in less than 1 in 20 cases) there may be blood vessel and heart valve abnormalities such as dilation of the aorta or mitral valve or tricuspid valve prolapse. These seem to be mild and unlikely ever to be in need of intervention with medicines or surgical repair.
A variant of cEDS, so called ‘Classic-like’ is considered to be due to changes in the structural protein Tenascin.
Vascular EDS
The Vascular type of EDS is characterized by thin, translucent skin that bruises easily but is not necessarily particularly stretchy, and spontaneous dilation / rupture of arteries and organs (Byers et al, 2017). The problem lies in the production of type 3 collagen. There is also a characteristic facial appearance:
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Protruding eyes,
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Thin nose and lips,
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Sunken cheeks, and
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Small chin.
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Hypermobility is typically found in the small joints of the hands. Other (non skin) features akin to other forms of EDS may also be found such as hip dislocation and clubfoot. The major causes for concern in this condition arise because of fragility of the blood vessels, gut wall, and uterus. There is a risk for rupture of any of these structures, which may be life threatening.
About a quarter of individuals with vEDS experience significant medical problems by the time they are 20 years of age. More than 80% of individuals experience major problems by the age of 40. Because of this life expectancy is shortened in vEDS.
