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Ehlers-Danlos syndrome

Posted By Alan Hakim, March 19, 2017

This article 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). It is aimed at health and social care professionals and lay people and as quick guide to the variety of issues that might arise. At the bottom of this article we have also linked the reader to more information on the Ehlers-Danlos Support – UK (EDS-UK) website, and to the open access articles published in March 2017 under the American Journal of Medical Genetics, Seminars series.

Introduction

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.

The Different 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), 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.

Table 1 shows the 2017 classification of EDS.

Table 1: The Classification of the Ehlers-Danlos Syndromes, Inheritance Pattern, and Genetic Basis (Malfait et al, 2017)

  Clinical EDS subtype Abbreviation IP Genetic basis Protein
      IP = inheritance pattern; AD = autosomal dominant; AR = autosomal recessive; NMD = nonsense-mediated mRNA decay.
1 Classical EDS cEDS AD Major: COL5A1, COL5A1 Type V collagen
Rare: COL1A1 Type I collagen
c.934C>T, p.(Arg312Cys)
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) Type I collagen
4 Vascular EDS vEDS AD Major: COL3A1 Type III collagen
Rare: COL1A1 Type I collagen
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 AR ADAMTS2 ADAMTS-2
8 Kyphoscoliotic EDS kEDS AR PLOD1 LH1
FKBP14 FKBP22
9 Brittle Cornea syndrome BCS AR ZNF469 ZNF469
PRDM5 PRDM5
10 Spondylodysplastic EDS spEDS AR B4GALT7 β4GalT7
B3GALT6 β3GalT6
SLC39A13 ZIP13
11 Musculocontractural EDS mcEDS AR CHST14 D4ST1
DSE DSE
12 Myopathic EDS mEDS AD or AR COL12A1 Type XII collagen
13 Periodontal EDS pEDS AD C1R C1r
C1S C1s

 

Classical type.

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:

  • Non-traumatic / spontaneous onset atrophic scars
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.

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 type.

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:

  • Protruding eyes,
  • Thin nose and lips,
  • Sunken cheeks, and
  • Small chin.

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.

Hypermobile type.

This is the most common form of EDS (Tinkle et al, 2017). There is currently no known genetic marker for this variant of EDS.

The skin and joint features may be similar as those of Classical EDS but much less severe. Joint pain and fatigue also appear to be more common in this form of EDS. Other signs of tissue fragility such as hernias and varicose veins may also be found. Importantly, this type of EDS is not associated with weakness or rupture of major blood vessels or bowel wall, or with the more severe forms of scoliosis.

Table 2 describes the criteria for diagnosing hEDS. An individual must fulfill each of the 3 domains (Table 1). In the second domain they must fulfill at least 2 of the 3 descriptors (A, B and C) by achieving sufficient scores where relevant. The domains are summarized below.

Table 2. The diagnostic criteria for hEDS.

Domain 1

The presence of generalized joint hypermobility (based on the Beighton Score or 5-part questionnaire)

Domain 2

(A) – skin or fascia signs and/or pelvic floor concerns and/or Marfanoid features (having at least 5 of all the features mentioned

(B) a family history

(C) At least 1 of the following 3 presentations:

  • Musculoskeletal pain in 2 or more limbs recurring daily for at least 3 months, or
  • Widespread pain for ≥3 months, or
  • Recurrent joint dislocations in the absence of trauma –  3 or more atraumatic dislocations in the same joint, or atraumatic dislocations in 2 different joints occurring at different times, or medical confirmation of joint instability at 2 or more sites not related to trauma

Domain 3 The absence of any other underlying Heritable Disorder of Connective Tissue including other variants of EDS

The features that constitute Domain 2 A are:Skin/fascia

  • Unusually soft or velvety skin
  • Mild skin hyperextensibility
  • Unexplained striae such as striae distensae or rubrae
  • Bilateral piezogenic papules of the heel
  • Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosiderotic scars as seen in classical EDS
  • Recurrent or multiple abdominal hernia
  • Pelvic floor, rectal, and/or uterine prolapse in children, men or nulliparous women without predisposing medical condition

Marfanoid features:

  • Dental crowding and high or narrow palate
  • Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria
  • Arm span-to-height ≥1.05 AND/OR upper segment/lower segment ratio <0.89
  • Arachnodactyly, as defined in one or more of the following: (i) positive wrist sign (Steinberg sign) on both sides; (ii) positive thumb sign (Walker sign) on both sides; (iii) hand/height ratio > 11% on both sides; (iv) foot/height ratio > 15% on both sides
  • Aortic root dilatation with Z-score >+2 on echocardiograph

 

There are a number of more rare types of EDS, notably Atherochalasia, Dermatospraxis, and Kyphoscolitic (Brady et al, 2017). The reader is directed to the EDS-UK website for more information on these types of EDS by clicking HERE. Also, the references below are available as open access papers by clicking HERE.

Dr Alan J Hakim MA FRCP

Consultant Physician and Rheumatologist, Chief Medical Advisor and Trustee, HMSA

Revised March 2017 V.4. Date of review March 2018

 

References

Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. 2017. Ehlers–Danlos syndrome, classical type. Am J Med Genet Part C Semin Med Genet 175C:27–39.

Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer-Seebacher I, Kosho T, Mendoza-Londono R, Pope MF, Rohrbach M, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Zschocke J, Malfait F. 2017. The Ehlers–Danlos syndromes, rare types. Am J Med Genet Part C Semin Med Genet 175C:70–115.

Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, Johnson D, Pepin M, Robert L, Sanders L, Wheeldon N. 2017. Diagnosis, natural history, and management in vascular Ehlers–Danlos syndrome. Am J Med Genet Part C Semin Med Genet 175C:40–47.

Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. 2017. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet 175C:8–26.

Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H. 2017. Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet Part C Semin Med Genet 175C:48–69.

 

 


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