Ehlers–Danlos syndromes (EDS) are a group of genetic connective tissue disorders. Symptoms may include loose joints, joint pain, stretchy skin, and abnormal scar formation. These can be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.
|Individual with an EDS displaying skin hyperelasticity|
|Specialty||Medical genetics, rheumatology|
|Symptoms||Overly flexible joints, stretchy skin, abnormal scar formation|
|Complications||Aortic dissection, joint dislocations, osteoarthritis|
|Usual onset||Birth or early childhood|
|Types||Hypermobile, classic, vascular, kyphoscoliosis, arthrochalasia, dermatosparaxis, brittle cornea syndrome, others|
|Risk factors||Family history|
|Diagnostic method||Genetic testing, skin biopsy|
|Differential diagnosis||Marfan syndrome, cutis laxa syndrome, familial joint hypermobility syndrome|
|Prognosis||Depends on specific disorder|
|Frequency||1 in 5,000|
EDSs result from a mutation of some of more than 19 different genes. The specific gene affected determines the specific EDS. Some cases result from a new mutation occurring during early development, while others are inherited in an autosomal dominant or recessive manner. Typically, these mutations result in defects in the structure or processing of the protein collagen. Diagnosis is often based on symptoms and confirmed with genetic testing or skin biopsy. However, people may initially be misdiagnosed with hypochondriasis, depression, or chronic fatigue syndrome.
No cure is known. Treatment is supportive in nature. Physical therapy and bracing may help strengthen muscles and support joints. While some disorders result in a normal life expectancy, those that affect blood vessels generally result in a shorter life expectancy.
EDSs affect at least one in 5,000 people globally. The prognosis depends on the specific disorder. Excess mobility was first described by Hippocrates in 400 BC. The syndromes are named after two physicians, Edvard Ehlers from Denmark and Henri-Alexandre Danlos from France, who described them at the turn of the 20th century.
Signs and symptomsEdit
This group of disorders affects connective tissues across the body, with symptoms most typically present in the joints, skin, and blood vessels. Effects may range from mildly loose joints to life-threatening cardiovascular complications. Due to the diversity of subtypes within the EDS family, symptoms may vary widely between individuals diagnosed with an EDS.
Musculoskeletal symptoms include hyperflexible joints that are unstable and prone to sprain, dislocation, subluxation, and hyperextension. There can be an early onset of advanced osteoarthritis, chronic degenerative joint disease, swan-neck deformity of the fingers, and Boutonniere deformity of the fingers. Tearing of tendons or muscles may occur. Deformities of the spine, such as scoliosis (curvature of the spine), kyphosis (a thoracic hump), tethered spinal cord syndrome, and occipitoatlantoaxial hypermobility may also be present. There can also be myalgia (muscle pain) and arthralgia (joint pain), which may be severe and disabling. Trendelenburg's sign is often seen, which means that when standing on one leg, the pelvis drops on the other side. Osgood–Schlatter disease, a painful lump on the knee, is common as well. In infants, walking can be delayed (beyond 18 months of age), and bottom-shuffling instead of crawling occurs.
Individual with EDS displaying hypermobile metacarpophalangeal joints
The weak connective tissue causes fragile skin that tears and bruises easily and atrophic scars that look like cigarette paper. Redundant skin folds occur, especially on the eyelids. Redundant skin folds are areas of excess skin lying in folds. Other skin symptoms include molluscoid pseudotumors, especially on pressure points, petechiae, subcutaneous spheroids, livedo reticularis, and piezogenic papules are less common. In vascular EDS, skin can also be thin and translucent.
- Thoracic outlet syndrome
- Arterial rupture
- Valvular heart disease, such as mitral valve prolapse, creates an increased risk for infective endocarditis during surgery. This may progress to a life-threatening degree. Heart conduction abnormalities have been found in those with hypermobility form of EDS.
- Dilation and/or rupture (aneurysm) of ascending aorta
- Cardiovascular autonomic dysfunction such as postural orthostatic tachycardia syndrome
- Raynaud's phenomenon
- Varicose veins
- Heart murmur
- Heart conduction abnormalities
- Hiatal hernia
- Gastroesophageal reflux
- Poor gastrointestinal motility
- Gorlin's sign (touch tongue to nose)
- Anal prolapse
- Collapsed lung (spontaneous pneumothorax)
- Nerve disorders (carpal tunnel syndrome, acroparesthesia, neuropathy, including small fiber neuropathy)
- Insensitivity to local anesthetics.
- Arnold–Chiari malformation
- Platelet aggregation failure (platelets do not clump together properly)
- Pregnancy complications: increased pain, mild to moderate peripartum bleeding, cervical insufficiency, uterine tearing, or premature rupture of membranes.
- Eye: Near-sightedness, retinal tearing and retinal detachment, keratoconus, blue sclera, dry eye, Sjorgen's syndrome, lens subluxation, angiod streaks, epicanthal folds, strabismus, corneal scarring, brittle cornea syndrome, cataracts, cartoid-cavernous sinus fistulas, macular degeneration
- Cranial vertebral instability: caused by trauma(s) to the head and neck areas such as concussion and whiplash. Ligaments in neck are unable to heal properly, therefore, the neck structure does not have the ability to support the skull, which can then sink into the brain stem blocking the normal flow of cerebrospinal fluid, leading to issues related to the autonomic nervous system failing to work properly.
- Celiac disease may be associated with EDS. Also, it can be misdiagnosed as EDS due to common symptoms, including fatigue, pain, gastrointestinal complaints, or cardiovascular autonomic dysfunction.
Because it is often undiagnosed or misdiagnosed in childhood, some instances of EDSs have been mischaracterized as child abuse.
The pain associated with the disorders may be severe.
Every type of EDS, except the hypermobile type, can be positively tied to specific genetic variation.
- Collagen primary structure and collagen processing: ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2
- Collagen folding and collagen cross-linking: PLOD1, FKBP14
- Structure and function of myomatrix: TNXB, COL12A1
- Glycosaminoglycan biosynthesis: B4GALT7, B3GALT6, CHST14, DSE
- Complement pathway: C1R, C1S
- Intracellular processes: SLC39A13, ZNF469, PRDM5
Mutations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder. Inheritance patterns depend on the specific syndrome. Most forms of EDSs are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause a disorder. A few are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected by a disorder. It can also be an individual (de novo or "sporadic") mutation. Sporadic mutations occur without any inheritance.
A diagnosis can be made by an evaluation of medical history and clinical observation. The Beighton criteria are widely used to assess the degree of joint hypermobility. DNA and biochemical studies can help identify affected individuals. Diagnostic tests include collagen gene-mutation testing, collagen typing via skin biopsy, echocardiogram, and lysyl hydroxylase or oxidase activity. However, these tests are not able to confirm all cases, especially in instances of an unmapped mutation, so clinical evaluation remains important. If multiple individuals in a family are affected, performing prenatal diagnosis may be possible using a DNA information technique known as a linkage study. Knowledge about EDSs among all kinds of practitioners is poor. Research is ongoing to identify genetic markers for all types.
As of 2017, 13 EDSs had been characterized, with a significant overlap in features.
Hypermobile EDS (hEDS, formerly categorized as type 3) is mainly characterized by hypermoblity that affects both large and small joints. It may lead to frequent joint subluxations (partial dislocations) and dislocations. In general, people with this skin that is soft, smooth, velvety, that bruises easily, and chronic muscle and/or bone pain. There is no known mutation that causes this form of EDS. It affects the skin less than other forms. It has no available genetic test.
Classical EDS (cEDS, formerly categorized as type 1) is charzcterized by extremely elastic skin that is fragile and bruises easily, that has wide, atrophic scars (flat or depressed scars); and hypermobility of the joints. Molluscoid pseudotumors (calcified hematomas that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) also are seen often. Sometimes, motor development is delayed and hypotonia occurs. The mutation causing this type of EDS is in the genes COL5A2, COL5A, and less frequently COL1A1. It involves the skin more than hEDS.
Vascular EDS (vEDS, formerly categorized as type 4) is identified by skin that is thin, translucent, extremely fragile, and bruises easily. It is also characterized by fragile blood vessels and organs that can easily rupture. Affected people are frequently short, and have thin scalp hair. It also has characteristic facial features including large eyes, an undersized chin, sunken cheeks, a thin nose and lips, and ears without lobes. Joint hypermobility is present, but generally confined to the small joints (fingers, toes). Other common features include club foot, tendon and/or muscle rupture, acrogeria (premature aging of the skin of the hands and feet), early onset varicose veins, pneumothorax (collapse of a lung), recession of the gums, and a decreased amount of fat under the skin. It can be caused by the mutations in the COL3A1 gene.
Kyphoscoliosis EDS (kEDS, formerly categorized as type 6) is associated with severe hypotonia at birth, delayed motor development, progressive scoliosis (present from birth), and scleral fragility. People may also have easy bruising, fragile arteries that are prone to rupture, unusually small corneas, and osteopenia (low bone density). Other common features include a "marfanoid habitus" which is characterized by long, slender fingers (arachnodactyly), unusually long limbs, and a sunken chest (pectus excavatum) or protruding chest (pectus carinatum). It can be caused by mutations in the gene PLOD1, or rarely, in the FKBP14 gene.
Arthrochalasia EDS (aEDS, formerly categorized as types 7A & B) is characterized by severe joint hypermobility and congenital hip dislocation. Other common features include fragile, elastic skin with easy bruising, hypotonia, kyphoscoliosis (kyphosis and scoliosis), and mild osteopenia. Type-I collagen is usually affected. It is very rare, with about 30 cases reported. It is more severe than the hypermobility type. Mutations in the genes COL1A1 and COL1A2 cause it.
Dermatosparaxis EDS (dEDS, formerly categorized as type 7C) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; hypermobility ranging from mild to serious; and hernias. Mutations in the ADAMTS2 gene cause it. It is extremely rare, with around 10 cases reported.
Brittle cornea syndrome is characterized by the progressively thinning of the cornea, early-onset progressive keratoglobus or keratoconus, nearsightedness, hearing loss, and blue sclerae. Classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often. It has two types. Type 1 occurs due to mutations in the ZNF469 gene. Type 2 is due to mutations in the PRDM5 gene.
Classical-like EDS (clEDS) is characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath).
Spondylodysplastic EDS (spEDS) is characterized by short stature (progressive in childhood), muscle hypotonia (ranging from severe congenital, to mild later-onset), and bowing of limbs.
Musculocontractural EDS (mcEDS) is characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, bruising, skin fragility with atrophic scars, and increased palmar wrinkling.
Myopathic EDS (mEDS) is characterized by congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures (joints of the knee, hip and elbow), and hypermobility of distal joints (joints of the ankles, wrists, feet and hands).
Periodontal EDS (pEDS) is characterized by severe and intractable periodontitis of early onset (childhood or adolescence), lack of attached gingiva, pretibial plaques, and family history of a first-degree relative who meets clinical criteria.
Cardiac-valvular EDS (cvEDS) is characterized by severe progressive cardiac-valvular problems (aortic valve, mitral valve), skin problems (hyperextensibility, atrophic scars, thin skin, easy bruising), and joint hypermobility (generalized or restricted to small joints).
Until 1997, the classification system for EDS included 10 specific types, and also acknowledged that other extremely rare types existed. At this time, the classification system underwent an overhaul and was reduced to six major types using descriptive titles. Genetic specialists recognize that other types of this condition exist, but have only been documented in single families. Except for hypermobility (type 3), the most common type of all ten types, some of the specific mutations involved have been identified and they can be precisely identified by genetic testing; this is valuable due to a great deal of variation in individual cases. However, negative genetic test results do not rule out the diagnosis, since not all of the mutations have been discovered; therefore, the clinical presentation is very important.
Forms of EDSs in this category may present with soft, mildly stretchable skin, shortened bones, chronic diarrhea, joint hypermobility and dislocation, bladder rupture, or poor wound healing. Inheritance patterns in this group include X-linked recessive, autosomal dominant, and autosomal recessive. Examples of types of related syndromes other than those above reported in the medical literature include:
- – type 5
- – type 8 – unspecified gene, locus 12p13
- – type 10 – unspecified gene, locus 2q34
- – Beasley–Cohen type
- B4GALT7 – progeroid form –
- – type unspecified
- CHST14 – D4ST1-deficient Ehlers–Danlos syndrome (adducted thumb-clubfoot syndrome)
Several disorders share some characteristics with EDSs. For example, in cutis laxa, the skin is loose, hanging, and wrinkled. In an EDS, the skin can be pulled away from the body, but is elastic and returns to normal when let go. In Marfan syndrome, the joints are very mobile and similar cardiovascular complications occur. People with an EDSs tend to have a "marfanoid" appearance (e.g., tall, skinny, long arms and legs, "spidery" fingers). However, physical appearance and features in several EDSs also have characteristics including short stature, large eyes, and the appearance of a small mouth and chin, due to a small palate. The palate can have a high arch, causing dental crowding. Blood vessels can sometimes be easily seen through translucent skin, especially on the chest. The genetic connective tissue disorder, Loeys-Dietz syndrome, also has symptoms that overlap with EDSs.
In the past, Menkes disease, a copper metabolism disorder, was thought to be an EDS. People are not uncommonly misdiagnosed with fibromyalgia, bleeding disorders, or other disorders that can mimic EDS symptoms. Because of these similar disorders and complications that can arise from an unmonitored case of an EDS, a correct diagnosis is important. Pseudoxanthoma elasticum (PXE) is worth consideration in diagnosis.
No cure is known for Ehlers–Danlos syndromes; treatment is supportive. Close monitoring of the cardiovascular system, physiotherapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing, casting) may be helpful. This can help with stabilizing the joints and preventing injury. Orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances, although individuals are advised not to become dependent on them until other mobility options have been exhausted. People should avoid activities that cause the joint to lock or overextend.
A physician may prescribe casting to stabilize joints. Physicians may refer a person to an orthotist for orthotic treatment (bracing). Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints.
Aquatic therapy promotes muscular development and coordination. With manual therapy, the joint is gently mobilized within the range of motion and/or manipulations. If conservative therapy is not helpful, surgical joint repair may be necessary. Medication to decrease pain or manage cardiac, digestive, or other related conditions may be prescribed. To decrease bruising and improve wound healing, some people have responded to vitamin C. Special precautions are often taken by medical care workers because of the sheer number of complications that tend to arise in people with EDS. In vascular EDSs, signs of chest or abdominal pain are considered trauma situations.
Cannabinoids and medical marijuana have shown some efficacy in reducing pain levels.
In general, medical intervention is limited to symptomatic therapy. Before pregnancy, peoples with an EDS should have genetic counseling and familiarize themselves with the risks to their own bodies that pregnancy poses. Children with an EDS should be provided with information about their disorder so they can understand why they should avoid contact sports and other physically stressful activities. Children should be taught that demonstrating the unusual positions that they can maintain due to loose joints should not be done, as this may cause early degeneration of the joints. Emotional support along with behavioral and psychological therapy can be useful. Support groups can be immensely helpful for peoples dealing with major lifestyle changes and poor health. Family members, teachers, and friends should be informed about EDSs so they can accept and assist the child.
The instability of joints, leading to (sub)luxations and joint pain, often require surgical intervention in people with an EDS. Instability of almost all joints can happen, but appear most often in the lower and upper extremities, with the wrist, fingers, shoulder, knee, hip, and ankle being most common.
Common surgical procedures are joint debridement, tendon replacements, capsulorraphy, and arthroplasty. After surgery, the degree of stabilization, pain reduction, and people's satisfaction can improve, but surgery does not guarantee an optimal result: affected peoples and surgeons report being dissatisfied with the results. Consensus is that conservative treatment is more effective than surgery, particularly since people have extra risks of surgical complications due to the disease. Three basic surgical problems arise due to an EDS: the strength of the tissues is decreased, which makes the tissue less suitable for surgery; the fragility of the blood vessels can cause problems during surgery; and wound healing is often delayed or incomplete. If considering surgical intervention, seeking care from a surgeon with extensive knowledge and experience in treating people with an EDS and joint hypermobility issues would be prudent.
Local anesthetics, arterial catheters, and central venous catheters cause a higher risk of bruise formation in people with an EDS. People with EDSs also show a resistance to local anaesthetics. Resistance to xylocaine and bupivacaine is not uncommon, and carbocaine tends to work better in people with an EDS. Special recommendations for anesthesia in people with an EDS are prepared by orphananesthesia and deal with all aspects of anesthesia for people with an EDS. Detailed recommendations for anesthesia and perioperative care of people with an EDS should be used to improve safety.
Surgery in people with an EDS requires careful tissue handling and a longer immobilization afterward.
The outcome for individuals with EDS depends on the specific type of EDS they have. Symptoms vary in severity, even in the same disorder, and the frequency of complications varies. Some people have negligible symptoms, while others are severely restricted in daily life. Extreme joint instability, chronic musculoskeletal pain, degenerative joint disease, frequent injuries, and spinal deformities may limit mobility. Severe spinal deformities may affect breathing. In the case of extreme joint instability, dislocations may result from simple tasks such as rolling over in bed or turning a doorknob. Secondary conditions such as autonomic dysfunction or cardiovascular problems, occurring in any type, can affect prognosis and quality of life. Severe mobility-related disability is seen more often in hypermobile EDS than in classical EDS or vascular EDS.
Although all EDSs are potentially life-threatening, most people have a normal lifespan. However, those with blood-vessel fragility have a high risk of fatal complications, including spontaneous arterial rupture, which is the most common cause of sudden death. The median life expectancy in the population with vascular EDSs is 48 years.
Ehlers–Danlos syndromes are inherited disorders estimated to occur in about one in 5,000 births worldwide. Initially, prevalence estimates ranged from one in 250,000 to 500,000 people, but these estimates were soon found to be too low, as more was studied about the disorders, and medical professionals became more adept at diagnosis. EDSs may be far more common than the currently accepted estimate due to the wide range of severities with which the disorder presents.
The prevalence of the disorders differs dramatically. The most commonly occurring is hypermobile EDS, followed by classical EDS. The others are very rare. For example, fewer than 10 infants and children with dermatosparaxis EDS have been described worldwide.
Some EDSs are more common in Ashkenazi Jews. For example, the chance of being a carrier for dermatosparaxis EDS is one in 248 in Ashkenazi Jews, whereas the prevalence of this mutation in the general population is one in 2,000.
Society and cultureEdit
Many sideshow performers have an EDS. Several of then were billed as the Elastic Skin Man, the India Rubber Man, and Frog Boy. They included such well-known individuals (in their time) as Felix Wehrle, James Morris, and Avery Childs. Two performers with EDS currently hold world records. Contortionist Daniel Browning Smith has hypermobile EDS and holds the current Guinness World Record for the most flexible man as of 2018, while Gary "Stretch" Turner (shown right), sideshow performer in the Circus Of Horrors, has held the current Guinness World Record for the most elastic skin since 1999, for his ability to stretch the skin on his stomach 6.25 inches.
Actress Cherylee Houston has hypermobile EDS and uses a wheelchair; she was the first full-time disabled actress on Coronation Street. Drag queen Yvie Oddly confirmed in an interview that she has EDS.
Ehlers–Danlos-like syndromes have been shown to be hereditary in Himalayan cats, some domestic shorthair cats, and in certain breeds of cattle. It is seen as a sporadic condition in domestic dogs. It has a similar treatment and prognosis. Animals with the condition should not be bred, as the condition can be inherited.
Degenerative suspensory ligament desmitis (DSLD) is a similar condition seen in many breeds of horses. It was originally notated in the Peruvian Paso and thought to be a condition of overwork and older age. However, DSLD is being recognized in all age groups and all activity levels. It has even been noted in newborn foals.The latest research has led to the renaming of the disease as equine systemic proteoglycan accumulation, after the possible systemic and hereditary components being delineated by the University of Georgia.
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