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Ehlers-Danlos Syndrome

Last updated March 19, 2018

Approved by: Maulik P. Purohit MD, MPH

Ehlers-Danlos Syndrome (EDS) is a hereditary connective tissue disorder caused by abnormalities in the formation of collagen, an important and the most abundant protein in the body.


What are the other Names for this Condition? (Also known as/Synonyms)

  • Cutis Hyperelastica
  • EDS (Ehlers-Danlos Syndrome)
  • Ehlers-Danlos Disease

What is Ehlers-Danlos Syndrome? (Definition/Background information)

  • Ehlers-Danlos Syndrome (EDS) is a hereditary connective tissue disorder caused by abnormalities in the formation of collagen, an important and the most abundant protein in the body
    • Connective tissue is made up of structural proteins known as collagens and fibroblast cells, which are arranged in rows
    • These tissues connect bone-bone and muscle-bone, and give strength, support, and elasticity to various structures of the body, like skin, joints, and walls of blood vessels
    • There are 3 types of connective tissue, namely, tendons, ligaments and cartilages
  • The disease occurs worldwide at a frequency of approximately 1 in 5,000. Both genders and all racial and ethnic groups may be affected by this disorder
  • Based on the cause, symptoms, and pattern of inheritance, EDS is classified into the following six major types:
    • Classic or classical type: It is caused by COL5A1 or COL5A2 gene mutation. This type is characterized by excessive elasticity of skin, easy bruising, extreme mobility of joints and tumor-like growths on skin
    • Hypermobility type: The cause of this type is unknown in most cases. In minority of cases, it is caused by mutation(s) in the TNXB gene. The condition is characterized by extreme mobility of both large and small joints
    • Vascular type: It is caused by mutation(s) in the COL3A1 gene. The condition is characterized by thin skin, fragile arteries, and organs prone to rupture, and reduced subcutaneous fat
    • Kyphoscoliotic type: It is caused by mutation(s) in the PLOD1 gene, and the condition is characterized by low muscle tone at birth and progressive scoliosis
    • Arthrochalasia type: It is caused by COL1A1 and COL1A2 gene mutation(s) and has symptoms overlapping with the hypermobility and kyphoscoliosis types of EDS
    • Dermatosparaxis type: ADAMTS2 gene mutations cause this type. It is manifested by the presence of saggy and fragile skin
  • In addition to the six major subtypes, some rare forms of EDS have also been reported that include:
    • Progeroid type: B4GALT1 mutation(s) cause this type of EDS. In this condition, the hair, bones, and skin are affected; individuals appear older than their biological age
    • Cardiac valvular type: COL1A2 gene mutations cause thus type of EDS. Apart from hypermobility and loose skin, this type is characterized by defects in the heart valves
    • Periodontitis type: The gene mutation(s) responsible for this form of EDS is not known. The symptoms are similar to the classical form, with progressive dental issues noted as additional signs of this disorder
    • Dysfibronectinemic type: The gene mutation(s) responsible for this form of EDS is not known. The disorder is characterized by platelet dysfunction
    • Types 5 (type V): The mutations causing this type are not characterized yet. Extremely flexible skin, short stature, and fleshy tumor-like growths are some specific symptoms of this form of type 5 EDS
  • While some subtypes follow an autosomal dominant pattern of inheritance, gene mutations in the other forms of EDS are inherited in an autosomal recessive fashion. The EDS type 5 is inherited in an X-linked manner
  • Irrespective of the form of EDS, extreme joint flexibility, susceptibility for joint dislocations, loose skin, and a tendency to bruise easily are some features of Ehlers-Danlos Syndrome
  • The diagnosis is made by physical examination, symptom assessment, evaluation of family medical history, collagen typing, and molecular genetic testing to ascertain certain gene mutations. Individual subtypes may require further testing of bones, teeth, heart, and internal organs
  • Major blood vessel rupture, aortic dissection, premature arthritis, premature loss of teeth, and damage to internal organs are some potential complications of Ehlers-Danlos Syndrome. The treatment options involve medications for pain and blood pressure, physical therapy, and surgery to correct bone dislocations
  • The prognosis of the condition depends on the subtype, severity of symptoms, and overall health of an affected individual. In most cases, individuals have a normal life span and intelligence. In rare cases, such as in the vascular form, sudden death is a possibility 
  • Since most EDS cases are caused by inherited gene mutations, there are presently no guidelines available to prevent the condition. However, if there is a family history of this disorder, prospective parents may benefit from testinsg for gene mutations followed by genetic counseling

Who gets Ehlers-Danlos Syndrome? (Age and Sex Distribution)

  • Ehlers-Danlos Syndrome occurs worldwide, at a frequency of approximately 1:5,000
  • The prevalence of the different forms of EDS, where known, is as follows:
    • Classical type - 1:20,000 to 1:40,000
    • Hypermobility type - 1:10,000 to 1:15,000
    • Vascular type - it is rare and the prevalence rate is about 1:250,000
    • Kyphoscoliotic type - it is very rare; only about 60 cases are reported worldwide
    • Arthrochalasia type - it is very rare; only about 30 cases are reported in the scientific literature worldwide
    • Dermatosparaxis type - it is extremely rare; only about a dozen cases (infantile and juvenile) are reported
    • Cardiovalvular type - the frequency of occurrence is less than 1:1,000,000
    • Dysfibronectinemic type - it is extremely rare; siblings in one family have been reported with this type of EDS
    • Type 5 - extremely rare type; only two affected families are reported in the scientific literature
  • EDS can affect both genders, all races and ethnic groups
  • The EDS type V, however, occurs predominantly in males, owing to its X-linked inheritance pattern
  • Depending on the form and severity of the condition, symptoms may be present at birth, or manifest themselves later in life. Typically, individuals with milder symptoms get diagnosed later during their adulthood

What are the Risk Factors for Ehlers-Danlos Syndrome? (Predisposing Factors)

The following are some known risk factors for Ehlers-Danlos Syndrome:

  • A family history of the EDS
  • Having parents who are close blood relatives (such as first cousins)

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Ehlers-Danlos Syndrome? (Etiology)

Ehlers-Danlos Syndrome is an inherited disorder caused predominantly by heritable gene mutations. The genes involved in the different forms of EDS are different, and are given below:

  • Classical type: It is caused by mutation(s) in the COL5A1 or COL5A2 genes 
  • Vascular type: It is caused by mutation(s) in the COL3A1 gene
  • Arthrochalasia type: COL1A1 or COL1A2 gene mutations(s) cause this form of EDS
    • The COL1A1, COL1A2, COL3A1, COL5A1 and COL5A2 genes code for collagen proteins, which, in combination with similar proteins, form mature collagen molecules and matrix. The proper assembly of the collagen matrix provides structural rigidity and functional flexibility to connective tissue
    • A mutation in any one of the genes can lead to abnormalities in the assembly of the collagen matrix, causing different forms of the condition. The gene mutations are inherited in an autosomal dominant fashion
  • Hypermobility type: In most cases, the cause of this form of EDS is not known. In a few cases, mutation(s) in the TNXB gene is reported
    • This gene codes for tenascin-X, a protein involved in the synthesis and assembly of some types of collagen. Tenascin-X, thus, plays an important role in the organization and structural integrity of connective tissue
    • A mutation in this gene may lead to a dysfunctional product, resulting in symptoms of EDS
    • The TNXB gene mutations are inherited in an autosomal dominant manner
  • Kyphoscoliotic type: It is caused by mutations in the PLOD1 gene
    • This gene codes for an enzyme called lysyl hydroxylase 1. This enzyme catalyzes the conversion of lysine (an amino acid) to hydroxylysine
    • Hydroxylysine is crucial for establishing cross-links between collagen fibers, thus contributing to the strength of connective tissue
    • A mutation in PLOD1 gene may compromise the structure and function of the enzyme, resulting in disorders such as EDS
    • The mutation is inherited in an autosomal recessive pattern
  • Dermatosparaxis type: It is caused by mutation(s) in the ADAMTS2 gene
    • This gene codes for the enzyme called “disintegrin and metalloproteinase with thrombospondin motifs-2” or ADAMTS2 enzyme
    • The enzyme catalyzes the conversion of collagen precursor molecules (known as procollagen) to collagen, by shortening them. This process facilitates the assembly of collagen molecules into the fibrils, to render strength and flexibility to connective tissue
    • Therefore, a mutation in this gene interferes with the formation of mature collagen molecules, disrupting the assembly of collagen fibrils. This results in disorders such as EDS
    • Mutations in ADAMTS2 gene are inherited in an autosomal recessive manner
  • Progeroid type: Mutations in B4GALT1 gene cause this type of EDS
    • This gene codes for an enzyme called beta-1,4-galactosyltransferase 1. This enzyme is localized inside the cellular organelle called Golgi bodies, as well as on the cell surface. This enzyme plays an important role in the production of collagen
    • A mutation in the gene disrupts collagen formation, resulting in symptoms associated with the progeroid type of EDS
    • B4GALT1 gene mutations are inherited in an autosomal recessive pattern
  • Cardiac valvular type: It is caused by mutations in the COL1A2 gene
    • As mentioned above, this gene is involved in the proper assembly of the collagen matrix. Mutations in COL1A2 gene disrupt collagen organization, leading to symptoms of the condition
    • This rare form of EDS is inherited in an autosomal recessive pattern
  • Periodontitis type: The gene mutations causing this type of EDS are not well-characterized
  • Dysfibronectinemic type: The gene mutations responsible for this subtype are not known
  • Type 5: The mutations causing this type of EDS are not known. However, the disorder is known to be inherited in an X-linked manner

Autosomal dominant inheritance pattern: In this type of inheritance, a single copy of a defective gene in every cell of an individual is sufficient to cause the condition. Typically, one inherits the condition from an affected parent.

Autosomal recessive inheritance pattern: In this type of inheritance, an individual must possess both copies of the causative gene in the defective form in every cell of his/her body for the condition to manifest itself. An affected individual inherits one defective copy from each parent. The parents are carriers of the condition and are generally not affected.

X-linked inheritance pattern: In this type of inheritance, the defective gene is carried on the X chromosome. Females have two X chromosomes, and the unaffected gene copy masks the effects of a defective gene copy. However, since males have only one X chromosome inherited from their mother, the defective gene is expressed in them, causing the condition.

It is possible for EDS to develop without any family history of the disorder. In such cases, sporadic mutations may be the cause of development of the condition.

What are the Signs and Symptoms of Ehlers-Danlos Syndrome?

The symptoms of Ehlers-Danlos Syndrome can vary in extent and severity, depending on the specific form of the disorder an individual has. However, there are a few symptoms that may be common to all the subtypes of EDS, and these are as follow:

  • Loose, elastic skin; abnormally thin skin
  • Tendency to bruise easily
  • “Cigarette paper” scars (scarring of skin owing to abnormal healing of wounds)
  • Degeneration and parchment-like (papyraceous) scarring of skin, which may expand 
  • Loose joints (laxity of joints)
  • Overly flexible joints: A range of movement beyond what is normally observed in unaffected individuals
  • Joint pain
  • A tendency to develop early-onset osteoarthritis
  • Vulnerability to joint dislocations
  • Thin and fragile blood vessels may predispose an individual to hemorrhages
  • Fragile internal organs and other tissues
  • Delayed wound healing

The signs and symptoms specific to the various subtypes of EDS include:

Classical type:

  • Smooth skin (“velvety”)
  • Formation of hard lumps under the skin, called calcified spheroids. These lumps are mobile and can move easily beneath the skin
  • Tumor-like growths on skin, called molluscoid pseudotumors
  • Flat feet
  • Low muscle tone (hypotonia)
  • Repeated bruising in the same location
  • Hiatal hernia or protrusion of a part of stomach through the diaphragm wall
  • Prolapse or shifting of internal organs
  • Deformed mitral valve in the heart
  • Dilated aorta, in rare cases
  • Complications after surgery, which may include
    • Hernia due to weak tissues and membranes
    • Opening of the surgical site wound, owing to separation of tissues (dehiscence)

Hypermobility type:

  • Smooth, velvety skin
  • Extreme flexibility of large as well as small joints
  • Extreme skin elasticity

Vascular type:

  • Extreme sensitivity to bruising
  • Prominent veins visible under very translucent skin
  • Vascular malformations such as abnormal connections between arteries and veins (arteriovenous fistula)
  • Weakening of arterial walls
  • Formation of aneurysms
  • Vulnerability to spontaneous bleeding due to rupture of arteries 
  • Low levels of subcutaneous fat in face and limbs
  • Abnormal facial features such as:
    • Pinched nose
    • High cheekbones
    • Thin lips
    • Malformed earlobes
    • Protruding eyes
  • Clubfoot
  • Varicose veins’ formation at a young age
  • Intestinal rupture
  • Collection of blood and air in the chest cavity (penumohemothorax)
  • Dehiscence (wound layer separation during or after surgery)
  • In pregnant women with this condition, the following may be observed:
    • Bleeding from uterine arteries
    • Uterine rupture
    • Uterine tearing and rupture during childbirth

Kyphoscoliotic type: The symptoms can be present at birth

  • Curved spine, which worsens with time
  • Low muscle tone
  • Reduced bone mass (osteopenia)
  • Spontaneous rupture of arteries
  • Eye abnormalities such as the following:
    • Small cornea
    • Fragility of membrane covering the eyeball (sclera)
    • Vulnerability to corneal rupture
    • Retinal tear or detachment

Arthrochalasia type: The symptoms can be present at birth

  • Hip dislocation at birth
  • Curved spine
  • Reduced bone mass

Dermatosparaxis type:

  • Sagging skin
  • Protrusion of soft tissues through a weakening in the abdominal wall (inguinal hernia) 
  • Protrusion of intestine through a weak point in the muscles surrounding the navel (umbilical hernia)

Progeroid type:

  • Wasting of scar tissue on skin
  • Reduced bone mass
  • An aged appearance due to:
    • Formation of wrinkles on facial skin
    • Sparse hair on the scalp
  • Abnormal development of forearms and elbows; bowed legs
  • Short stature
  • Delayed intellectual development

Cardiac valvular type:

  • Mitral valve prolapse  
  • Backflow of blood into the heart (mitral valve regurgitation)

Periodontitis type:

  • Undersized jaw (micrognathia)
  • Extremely flexible jaw, leading to jaw dysfunction (temporomandibular joint dysfunction)
  • Abnormal plaque formation
  • Severe gum infection and tooth decay
  • Premature loss of teeth

Dysfibronectinemic type:

  • Abnormality in blood platelets
  • Abnormal bleeding into skin
  • Mitral valve prolapse

Type 5:

  • Extremely thin skin; highly-elastic skin
  • Formation of fleshy tumor-like growths (molluscoid pseudotumors) on skin
  • Short stature

How is Ehlers-Danlos Syndrome Diagnosed?

The diagnosis of Ehlers-Danlos Syndrome is made with the help of the following tests and exams:

  • A thorough physical examination and an assessment of symptoms
  • Evaluation of personal and family medical history
  • Measurement of skin hyperextensibilty, by pulling skin up till resistance is registered
  • Beighton scale hypermobility testing for joints
  • Collagen typing, using a skin biopsy sample
  • Collagen skin mutation testing
  • Electron microscopic observation of skin sample
  • Blood tests for checking the following parameters:
    • Blood cell count
    • Platelet abnormalities
    • Lysyl hydroxylase or oxidase activity
  • Imaging tests such as X-ray, computed tomography (CT) scanning, or magnetic resonance imaging (MRI):
    • To visualize bone deformities such as scoliosis and loss of bone mass
    • For structural abnormalities of the heart, along with echocardiography
    • To monitor aneurysm
  • Genetic testing to confirm mutations in genes that cause EDS

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Ehlers-Danlos Syndrome?

The following are some potential complications that may develop in individuals with different forms of Ehlers-Danlos Syndrome:

  • Bruising of skin (often at the same locations) and permanent scarring 
  • Disintegration of scar tissue
  • Joint pain; early-onset arthritis
  • Repeated joint dislocations
  • Short stature
  • Developmental delays
  • Loss of teeth at an early age
  • Delayed wound healing
  • Spontaneous rupture of blood vessels
  • Intestinal rupture
  • Rupture of eyeball
  • Aortic root dilatation (enlargement of the aorta)
  • Mitral valve regurgitation (blood flowing back into the heart)
  • Collapsed lungs (pneumothorax)
  • Progressive loss of motor function 
  • Uterine or arterial rupture during pregnancy
  • Vaginal tear and uterine rupture at childbirth

How is Ehlers-Danlos Syndrome Treated?

The treatment for Ehlers-Danlos Syndrome is symptomatic, as there is no cure for the condition. Often, a coordinated effort by professionals from various specialties may be needed to help improve the quality of life of the affected individual.

The following are some options for treating the symptoms of EDS:

  • Medications for pain relief: The strength of medication will depend on the severity of pain
  • Medication to reduce blood pressure (necessitated by fragile blood vessels) such as the following:
    • Beta blockers
    • Angiotensin converting enzyme inhibitors
    • Calcium channel blockers
    • Diuretic pills
  • Proper and well-balanced nutrition
  • Vitamin C supplements may be recommended to aid in collagen synthesis and wound healing
  • Physiotherapy to strengthen muscles around weak joints
  • Braces to stabilize joints and minimize dislocations
  • Rarely, surgery to repair joints damaged by repeated dislocations may be performed, if necessary

How can Ehlers-Danlos Syndrome be Prevented?

Ehlers-Danlos Syndrome is a genetic condition, and therefore, there are no methods or guidelines available to prevent its occurrence.

  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • In individuals who are diagnosed with EDS, the following may be helpful in reducing injuries, dislocations, and bleeding:
    • Avoiding contact sports and other activities that may cause an injury
    • Wearing padding over joints that are vulnerable to dislocation
    • Maintaining proper dental hygiene using specialized soft toothbrush
    • Avoiding unnecessary surgical procedures, since wound healing may be compromised
    • If surgery or dental procedures are necessary, then taking precautions against bleeding before, during and after the surgery/procedure
    • Proper counseling and medical care for women before and during pregnancy, as well as during and after childbirth
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Ehlers-Danlos Syndrome

Regular medical screening at periodic intervals with tests and physical examinations are crucial and highly recommended.

What is the Prognosis of Ehlers-Danlos Syndrome? (Outcomes/Resolutions)

  • The prognosis of Ehlers-Danlos Syndrome is determined by the severity of the condition, and the overall health of the affected individual
  • The life expectancy of individuals affected by EDS is reported to be normal (with the exception of the vascular form)
  • However, since there is no cure for this condition, lifelong management with medication, physiotherapy, and other methods are necessary to have a better quality of life
  • Complications from vascular EDS, such as sudden rupture of blood vessels or organs can be fatal. The average lifespan of individuals with this form of EDS is consequently reduced, and is approximately 40 years

Additional and Relevant Useful Information for Ehlers-Danlos Syndrome:

Please visit our Congenital & Genetic Disorders Health Center for more physician-approved health information:

http://www.dovemed.com/diseases-conditions/congenital-genetic-disorders/

What are some Useful Resources for Additional Information?


References and Information Sources used for the Article:


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Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Sept. 28, 2017
Last updated: March 19, 2018