Ehlers-Danlos syndrome

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Ehlers-Danlos syndromes (EDS) is a group of inherited disorders that affects connective tissues — primarily skin, joints, and blood vessel walls. It is a genetic disease that causes a defect in the production and/or metabolism of collagen and other connective tissue abnormalities. It is characterized by joint hypermobility, skin hyperextensibility, and tissue fragility, and ranges widely in severity.

Symptoms and presentation

An 18 years old patient with EDS can extend his fingers back to almost touching the forearm due to hypermobile phalangeal joints.

Symptoms vary widely between individuals, based on the subtype of EDS they have. EDS affects connective tissues, which results in symptoms that range from mild joint effects to life-threatening complications.

• joint hypermobility (stretch further than normal)
• loose/unstable joints, prone to subluxations/dislocations
• joint pain
• joints that move beyond the normal range (hyperextensibility)
• early onset of arthritis
• soft, velvety-like skin
• fragile skin that tears or bruises easily
• severe scarring
• slow and poor wound healing
• development of molluscoid psuedo tumors
• musculoskeletal pain
• poor muscle tone (less common)

Subtypes

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  Hypermobile EDS, cEDS, and clEDS can be diagnosed using The Beighton Scoring System along with EDS Types criteria. Here, thumb reaches forearm in one of its measurements

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  Hyperelastic skin in a person with cEDS

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  Translucent skin in Vascular EDS (VEDS)

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  Atrophic scar found in cEDS, clEDS, Dermatosparaxis, and some other types

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  "Marfanoid habitus" (resembling Marfans Syndrome) long slender fingers of Kyphoscoliosis Type EDS

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  4 y/o diagnosed by swelling of eyelids, corneas protruded anteriorly, blue sclerae, high myopia, and keratoconus. EDS, Rare Types: Brittle Cornea Syndrome (BCS)

There are currently thirteen sub-types of EDS. These include six distinct types of EDS and sub-types, as well as five presentations that fit into an 'other' category. They are:

• Hypermobile EDS (hEDS) - the most dominant clinical manifestation; presents with joint hypermobility, resulting into dislocations, bruising and chronic pain, often out of proportion to physical and radiological findings.

• Classical (cEDS) and Classical-like (clEDS) presents with marked skin hyperextensibility, joint hypermobility, and in clEDS easy bruising.
• Vascular EDS (VEDS) and Cardiac-valvular EDS (cvEDS) - presents with arterial/intestinal/uterine fragility with possibility of arterial or organ rupture; often presents with thin or translucent skin with veins being visible thru the skin and in cvEDS severe progressive cardiac-valvular problems.
• Kyphoscoliosis Type - presents with scoliosis, joint laxity, and severe muscle hypotonia at birth; scoliosis is progressive and may result in the loss of the ability to walk in one's 20's or 30's. Other common features include a "marfanoid habitus" characterized by long, slender fingers; unusually long limbs; and a sunken chest or protruding chest.
• Arthrochalasia Type - presents with congenital hip dislocation and generalized joint hypermobility; may also have skin hyperextensibility, tissue fragility, kyphoscoliosis, and muscle hypotonia.
• Dermatosparaxis Type - presents with severe skin fragility and substantial bruising.
• Other Types - Brittle Cornea Syndrome (BCS); Spondylodysplastic EDS (spEDS),Musculocontractural EDS (mcEDS), Myopathic EDS (mEDS), Periodontal EDS (pEDS) - this category groups the rarest genetic presentations sometimes only seen in one family.

Prevalence

Ehlers-Danlos syndrome affects both males and females.

1 in 5,000 have some form of EDS worldwide. Hypermobile EDS (hEDS) and classical forms of EDS (cEDS) are most common. Hypermobile may affect as many as 1 in 5,000 to 20,000 people, while the classical type probably occurs in 1 in 20,000 to 40,000 people. Other forms are rare, often with only a few cases or affected families in the world.

Risk factors

Ehlers-Danlos syndrome is a hereditary disease cause by a genetic mutation in one or more of the connective tissue genes, especially those involved in the metabolism of collagen, an important protein found in muscle, skin, ligaments, tendons, cartilage, bones, blood vessels, and other body tissue.

Diagnosis

Diagnosis is made through physical examination which includes a test for hypermobility, such as the Beighton Scoring System or the Brighton criteria for EDS.

Pathophysiology

EDS is a diverse group of inherited connective-tissue disorders. Joint hypermobility, skin fragility, and hyperextensibility characterize the disorders. Collagen defect has been identified in at least six types.

The vascular form is characterized by a decreased amount of type III collagen. It is autosomal dominant (AD), one parent with a defective gene are needed to pass on this form of EDS and is caused by mutations in COL3A1. This results in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death.

In EDS types I and II, cEDS and clEDS, causative mutations may involved the COL5A1, COL5A2, and tenascin-X genes and are implied to be in the COL1A2 gene. "Although half of the mutations that cause Ehlers-Danlos syndrome types I and II are likely to affect the COL5A1 gene, a significant portion of the mutations result in low levels of mRNA from the mutant allele as a consequence of nonsense-mediated mRNA decay."

Kyphoscoliotic (type VI) is characterized by generalized joint laxity, skin fragility, and severe muscle hypotonia at birth. It is autosomal recessive (AR), both parents with defective genes are needed to pass on this form of EDS. More than 20 mutations are identified in the LH1 gene that contributes to LH deficiency and clinical EDS type VI.

Impaired wound healing is a typical feature of EDS.

Pediatric patients have deficiencies in three genes of glutathione S-transferase family (GSTM1, GSTT1, GSTP1).

Reduced activity of beta4GalT-7 is associated with the progeriform (causing children to age rapidly) EDS.

"Biallelic mutations in FKBP14 may result in a recessive form of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, hearing loss, and, possibly, an increased risk for vascular complications."

An EDS Types Chart with AD/AR inheritance pattern (IP), genetic basis, and protein involved are provided by The Ehlers Danlos Society.

Systems affected by EDS

Systems affected by EDS include:

• anxiety disorders and depression
• bladder
• bleeding
• brain and spine
• circulatory system, cardiovascular
• dental, oral, and voice problems
• digestive disorders
• diverticulitis
• heart and valve leakage
• hernia
• joint, musculoskeletal
• ocular
• reproductive
• skin
• subluxations and dislocations

Comorbidities & complications

ME/CFS

A 1999 case series by Dr. Peter Rowe of adolescents referred to his chronic fatigue syndrome clinic found 12 patients who also met the criteria for Ehlers-Danlos Syndrome and had orthostatic intolerance (postural orthostatic tachycardia or neurally-mediated hypotension). He concluded that “Among patients with CFS and orthostatic intolerance, a subset also has EDS.” He also found joint hypermobility (Beighton score > 4) in 60% of pediatric ME/CFS patients viruses 24% of healthy controls. A 2022 study by Rowe found that hypermobility did not show any association with other clinical characteristics of ME/CFS, despite it being a risk factor for the development of ME/CFS.

A Swedish study of 234 ME/CFS patients meeting the Canadian Consensus Criteria found that 49% of patients had hypermobility and 20% met the criteria for hEDS.

Other

• Dysautonomia
• Mast cell activation syndrome
• Postural orthostatic tachycardia syndrome
• Chiari malformation
• Syringomyelia
• Craniocervical instability
• Atlantoaxial instability

• Intracranial hypertension
• Kyphosis and Scoliosis
• Tethered cord syndrome
• Dystonia
• Tarlov cyst
• Mitral valve prolapse

Treatment

Medications

There is no cure for EDS and treatments aren’t limited to over-the-counter pain relievers such as acetaminophen (Tylenol and others) ibuprofen (Advil, Motrin IB, others), and naproxen sodium (Aleve). Prescription medications are used for acute injuries and chronic pain. Blood pressure medications are sometimes used to keep pressure low to relieve stress on vessels.

Physical therapy

Because dislocations occur in EDS, exercise to strengthen the muscles and stabilize joints are the primary treatment. Braces help prevent joint dislocations. However when patients with severe CFS/ME physical therapy must be done incrementally .

Surgical and other procedures

Surgery may be recommended to repair joints damaged by dislocations but connective tissue may not heal properly. Ruptured blood vessels or organs for patients with VEDS may also be necessary.

See also

• Collagen
• Joint hypermobility and hypermobility syndromes

Learn more

• Ehlers-Danlos Syndrome Toolkit
• Pregnancy, birth, feeding and hypermobile Ehlers-Danlos syndrome / hypermobility spectrum disorders

• 2016, Another Piece of the Puzzle: An ME/CFS/FM Patient Gets an Ehlers Danlos Syndrome Diagnosis
• Blood Vessels — Wall Structure of Arteries and Veins