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Ehlers-Danlos syndrome

Ehlers-Danlos syndrome (EDS) refers to a group of hereditary genetic diseases that affect the connective tissue, whose function is to provide cohesion to other body tissues and support many body parts such as skin, joints, blood vessels, and internal organs.

Due to incorrect function of the enzymes that synthesize collagen, the protein that binds the body’s tissues together, individuals affected by this syndrome usually present with joint hypermobility, skin hyperextensibility (easily stretched and damaged skin), and tissue fragility.

Other symptoms associated with EDS are joint pain, fatigue, delayed wound healing and scarring, flatfeet, soft and velvety skin, eyesight problems, etc.

Several different types of EDS have been described, with symptoms varying depending on which organs are the most affected. Moreover, the symptoms of each disease type may manifest with different degrees of severity, from moderate to very severe cases.

On the other hand, it is believed that approximately 50% of patients cannot be clearly classified into any of the defined categories and present with mixed symptoms of different types.

According to the classification by Villefranche, the following EDS types can be distinguished:

Classic EDS is mainly characterized by skin hyperextensibility, abnormal wound healing, and ligament hypermobility.

This type of EDS is characterized by the involvement of the following organs and tissues.

Skin

Skin in people affected with this type of EDS may have some of the following characteristics:

  • Easily stretched, returns to its initial position when released (skin hyperextensibility).
  • Soft and velvety texture.
  • Fragile, easily bruised and damaged.
  • Delayed wound healing.
  • Bluish hands and feet (acrocyanosis).
  • Lesions can appear at pressure sites such as the elbow and knee (moluscoid pseudotumors).
  • Small nodules or cysts, often movable, can be detected under the skin of forearms and shins (subcutaneous spheroids).
  • Protrusions in the heels may be visible when standing up and disappear when the feet are lifted (piezogenic papules).
  • Chilblains, injuries characterized by painful or itchy skin inflammation, are also frequent.

Fragile tissues

Multiple organs can be affected:

  • Cervical insufficiency during pregnancy, which may lead to inability to carry a pregnancy to term or until the fetus is viable.
  • Inguinal, umbilical, incisional, and hiatal hernias.
  • Recurrent rectal prolapse during early infancy.

Joints

Complications due to joint hypermobility:

  • Dislocation of the shoulder, patella, fingers, hips, radius, and collarbones, usually spontaneously resolved or easily reduced by the affected individual.
  • Feet deformities, such as congenital clubfoot or flatfoot, temporomandibular joint dysfunction, and osteoarthritis.

Neurological features

Primary muscle hypotonia may occur, leading to delayed motor development, ambulation problems, and minor motor alterations.

Fatigue and muscle cramps are relatively frequent and, in some cases, cerebrospinal fluid leaks have been identified as the cause of orthostatic hypotension and headache in individuals with classic EDS.

 

Cardiovascular system

Structural cardiac malformations are rare in classic EDS.

Hypermobility-type EDS is generally considered the least severe type, although major complications, mainly musculoskeletal, may occur.

 

Skin

  • Es suave o aterciopelada y puede ser levemente hiperextensible.
    Es común que en los talones sean visibles protuberancias que aparecen cuando se está de pie y desaparecen cuando el pie se levanta (pápulas piezogénicas).

Musculoskeletal system

  • Subluxations and dislocations are frequent and may occur spontaneously or as a result of mild trauma.
  • Sprained ankles and knees “buckling” are also common.
  • Osteoarthritis, a degenerative joint disease, occurs at an earlier age than in the general population.
  • Bone mineral density can be reduced with respect to the general population, leading to osteoporosis.

Pain

Chronic pain (different from acute pain caused by dislocations) is a serious complication of this disease and can be physically and psychologically incapacitating.

 

Hematology

Bruises occur easily, often without previous trauma or obvious injuries.

Slightly prolonged bleeding, nosebleeds, bleeding gums (particularly after teeth removal), and menometrorrhagia can also occur.

 

Gastrointestinal system

Functional gastrointestinal disorders such as gastroesophagic reflux and gastritis are common, although usually overlooked.

 

Cardiovascular system

Between 11% and 33% of individuals with classic and hypermobility-type EDS may show aortic root dilation, generally mild.

Severity seems to be much lower than in Marfan syndrome, and risk of aortic dissection is not increased in the absence of significant dilation.

Vascular-type EDS is particularly severe due to the possibility of rupture of arteries or organs.

It is defined by characteristic facial features (acrogeria or premature aging) in most patients, translucid skin with highly visible subcutaneous blood vessels in the torso and lower back, easy bruising, and severe arterial, digestive, and uterine complications that are rarely observed in other forms of EDS.

Vascular complications can affect all areas of the body, preferentially affecting medium- and large-diameter arteries, with frequent occurrence of vertebral and carotid artery dissection.

There is a high risk of recurrent colon perforation, and the risk of uterine or vascular rupture during pregnancy is increased.

Kyphoscoliosis-type EDS is characterized by:

  • Fragile, hyperextensible skin (easily stretched, returns to its initial position when released), thin scars, and easily bruised skin.
  • Generalized ligament laxity
  • Severe muscular hypotonia at birth.
  • Progressive scoliosis present at birth or during the first year of life.
  • Fragile sclera, with increased risk of globe rupture.

Intelligence and life expectancy are normal, but affected individuals are at risk of rupture of medium-caliber arteries and respiratory involvement if scoliosis is severe.

Arthrochalasia-type EDS is characterized by:

  • Generalized ligament hyperlaxity with recurrent luxations.
  • Congenital bilateral hip luxation.
  • Skin hyperextensibility, with easily stretched skin that returns to its initial position when released.
  • Fragile tissues.
  • Presence of atrophic scars.
  • Easy bruising.
  • Muscle hypotonia.
  • Kyphoscoliosis.
  • Mild osteopenia.

Dermatosparaxis-type EDS is characterized by:

  • Severe skin fragility; redundant or loose skin, soft and easily bruised.
  • Premature rupture of fetal membranes may occur.
  • Inguinal or umbilical hernias.
  • Wound scarring is not affected, and atrophic scars are not observed.

Based on the classification by Villefranche, the following table shows the type of inheritance and the genes related to the most common types of EDS.

According to data published by the Spanish National Ehlers Danlos Syndrome and Hyperlaxitude Association (ANSEDH), EDS is globally estimated to affect 1 in every 5,000-10,000 births.

It can affect both men and women, with no differences according to race or ethnicity. Symptoms of the disease commonly appear during childhood, although onset can occur later in some cases, becoming apparent during adulthood.

Los SED tipo Clásico, Hiperlaxitud y Vascular son más frecuentes que los SED tipo Artrocalasia, Cifoescoliosis y Dermatosparaxis.

Classic, hypermobility, and vascular EDS are more common than arthrochalasia-, kyphoscoliosis-, and dermatosparaxis-type EDS.
The incidences of the different types of EDS in the population are:

  • The classic type affects 1 in every 20,000 people.
  • The hypermobility type affects 1 in 5,000-20,000 people.
  • The vascular type affects 1 in 50,000-250,000 people.
  • The kyphoscoliosis type affects 1 in 100,000 people.
  • The arthrochalasia type has been described in 30 people worldwide.
  • The dermatoparaxis type has been described in 8 people worldwide.

In individuals diagnosed with EDS, medical follow-up of their case is essential to identify and prevent risks to their health derived from the disease.

On the other hand, a genetic counseling consultation is recommended to future parents who suffer from the disease or are aware of a history of the disease in the family, with the purpose of knowing the risk of transmitting the disease to their offspring, perform any genetic testing deemed necessary and take appropriate prevention measures.

ANSEDH – Spanish Ehlers-Danlos Sndrome and Hypermobility Association.

Orphanet – Portal for rare diseases and orphan drugs.

Red EDA – Ehlers Danlos Argentina.