Ehlers–Danlos syndromes

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Ehlers–Danlos syndromes
Ehlers-Danlos syndrome4.jpg
Individual with EDS displaying skin hyperelasticity
Specialty Medical genetics
Symptoms Overly flexible joints, stretchy skin, abnormal scar formation[1]
Complications Aortic dissection, joint dislocations, osteoarthritis[1]
Usual onset Birth or early childhood[2]
Duration Long term[3]
Causes Genetic[1]
Diagnostic method Genetic testing, skin biopsy[3]
Similar conditions Marfan syndrome, cutis laxa syndrome, familial joint hypermobility syndrome[3]
Treatment Supportive[4]
Prognosis Depends on the type[3]
Frequency 1 in 5,000[1]

Ehlers–Danlos syndromes (EDS) are a group of genetic connective tissue disorders.[1] Symptoms may include loose joints, stretchy skin, and abnormal scar formation.[1] These can be noticed at birth or in early childhood.[2] Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.[3][1]

EDS is due to a mutation in one of more than a dozen different genes.[1] The specific gene affected determines the type of EDS.[1] Some cases result from a new mutation occurring during early development while others are inherited in an autosomal dominant or recessive manner.[1] This results in defects in the structure or processing of collagen.[1] The diagnosis may be confirmed with genetic testing or a skin biopsy.[3] People may be misdiagnosed with hypochondriasis, depression, or chronic fatigue syndrome.[3]

There is no known cure.[4] Treatment is supportive in nature.[3] Physical therapy and bracing may help strengthen muscles and support joints.[3] While some types result in a normal life expectancy, those that affect blood vessels generally result in a shorter life expectancy.[4]

EDS affects about 1 in 5,000 people globally.[1] The prognosis depends on the specific type.[3] Excess mobility was first described by Hippocrates in 400 BC.[5] The syndrome is named after two physicians, Edvard Ehlers from Denmark and Henri-Alexandre Danlos from France, who described it at the turn of the 20th century.[6]

Signs and symptoms[edit]

Individual with EDS displaying hypermobile joints

Signs vary widely based on which type of EDS the patient has. In each case, however, the signs are ultimately due to faulty or reduced amounts of collagen. EDS typically affects the joints, skin, and blood vessels. Following is a list of major signs and symptoms.[citation needed]

Musculoskeletal[edit]

Skin[edit]

Cardiovascular[edit]

Other manifestations[edit]


Because it is often undiagnosed or misdiagnosed in childhood, some instances of Ehlers–Danlos syndrome have been mischaracterized as child abuse.[34]

The pain associated with this condition is a serious complication.[35]

Genetics[edit]

The collagen fibril and EDS. (a) Normal collagen fibrils are of uniform size and spacing. Fibrils from a patient with dermatosparaxis (b) show dramatic alterations in fibril morphology with severe effects on tensile strength of connective tissues. Patients with classical EDS (c) show composite fibrils. Fibrils from a TNX-deficient patient (d) are uniform in size and no composite fibrils are seen. TNX-null (e) fibrils are less densely packed and not as well aligned to neighboring fibrils.

Only some variations of Ehlers–Danlos can be positively identified as tied to specific genetic variation.

Mutations in the following genes can cause subtypes of the Ehlers–Danlos syndrome:

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.[citation needed]

Inheritance patterns depend on the type of Ehlers–Danlos syndrome. Most forms of the condition 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 the disorder. The minority are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected by the condition. It can also be an individual (de novo or "sporadic") mutation. Refer to the summary for each type of Ehlers–Danlos syndrome for a discussion of its inheritance pattern.[36]

Diagnosis[edit]

X-ray of a wrist with midcarpal instability

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 by a geneticist remains essential. If there are multiple affected individuals in a family, it may be possible to perform prenatal diagnosis using a DNA information technique known as a linkage study.[citation needed] There may be poor knowledge about EDS among practitioners.[37][38]

Classification[edit]

As of 2017 there are 13 types of Ehlers-Danlos syndromes, with a significant overlap in features.[39]

Hypermobile EDS - characterized primarily by joint hypermobility affecting both large and small joints, which may lead to recurrent joint dislocations and subluxations (partial dislocation). In general, people with this type have soft, smooth and velvety skin with easy bruising and chronic pain of the muscles and/or bones.[39]

Classical EDS - associated with extremely elastic (stretchy), smooth skin that is fragile and bruises easily; wide, atrophic scars (flat or depressed scars); and joint hypermobility. Molluscoid pseudotumors (calcified hematomas over pressure points such as the elbow) and spheroids (fat-containing cysts on forearms and shins) are also frequently seen. Hypotonia and delayed motor development may occur.[39]

Vascular EDS - characterized by thin, translucent skin that is extremely fragile and bruises easily. Arteries and certain organs such as the intestines and uterus are also fragile and prone to rupture. People with this type typically have short stature; thin scalp hair; and characteristic facial features including large eyes, a thin nose, and lobeless ears. 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.[39]

Kyphoscoliosis EDS - associated with severe hypotonia at birth, delayed motor development, progressive scoliosis (present from birth), and scleral fragility. Affected 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).[39]

Arthrochalasia EDS - 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.[39]

Dermatosparaxis EDS - associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; and hernias. Brittle Cornea Syndrome (BCS) characterized by thin cornea, early onset progressive keratoglobus; and blue sclerae.[39]

Classical-like EDS (clEDS) characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility (GJH) 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).[39]

Spondylodysplastic EDS (spEDS) characterized by short stature (progressive in childhood), muscle hypotonia (ranging from severe congenital, to mild later-onset), and bowing of limbs.[39]

Musculocontractural EDS (mcEDS) 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, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling.[39]

Myopathic EDS (mEDS) 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).[39]

Periodontal EDS (pEDS) 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.[39]

Cardiac-valvular EDS (cvEDS) 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).[39]

Differential diagnosis[edit]

There are several disorders that share some characteristics with Ehlers–Danlos syndrome. For example, in cutis laxa the skin is loose, hanging, and wrinkled. In 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 EDS tend to have a "Marfanoid" appearance (e.g., tall, skinny, long arms and legs, "spidery" fingers). However, physical appearance and features in several types of Ehlers–Danlos syndrome 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 EDS.[40]

In the past, Menkes disease, a copper metabolism disorder, was thought to be a form of Ehlers–Danlos syndrome. It is not uncommon for patients to be misdiagnosed with fibromyalgia, bleeding disorders or other disorders that can mimic EDS symptoms before a correct diagnosis is made. Because of these similar disorders and complications that can arise from an un-monitored case of EDS, a correct diagnosis is very important.[41] Pseudoxanthoma elasticum (PXE) is worth consideration in diagnosing a patient.[citation needed]

Management[edit]

There is no known cure for Ehlers–Danlos syndrome. Treatment is palliative. 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 prevent injury. Orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances, although it is advised that individuals not become entirely dependent on them until there are no other options for mobility. One should avoid activities that cause the joint to lock or overextend.[citation needed]

A physician may prescribe casting to stabilize joints. Physicians may refer a patient 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.[42][43]

There are different types of physiotherapy. Aquatic therapy promotes muscular development and coordination.[44] With manual therapy, the joint will be gently mobilized within the range of motion and/or manipulations.[42][43] If conservative therapy is not helpful, surgical repair of joints 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 patients have responded to ascorbic acid (vitamin C).[45] Special precautions are often taken by medical care workers because of the sheer amount of complications that tend to arise in EDS patients. In Vascular EDS, signs of chest or abdominal pain are to be considered trauma situations.[citation needed]

In general, medical intervention is limited to symptomatic therapy. Before pregnancy, patients with EDS should have genetic counseling and familiarize themselves with the risks to their own bodies that pregnancy poses. Children with EDS should be provided with information about the disorder so they can understand why contact sports and other physically stressful activities should be avoided. Children should be taught early on that demonstrating the unusual positions they can maintain due to loose joints should not be done as this may cause early degeneration of the joints. Patients may find it hard to cope with the drawbacks of the disease. In this case, emotional support and behavioral and psychological therapy can be useful. Support groups can be immensely helpful for patients dealing with major lifestyle changes and poor health. Family members, teachers, and friends should be informed about EDS so they can accept and assist the child.[citation needed]

Surgery[edit]

The instability of joints, leading to (sub)luxations and joint pain, often require surgical intervention in patients with Ehlers–Danlos syndrome. 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.[42]

Common surgical procedures are joint debridement, tendon replacements, capsulorraphy, and arthroplasty. Studies have shown that after surgery, degree of stabilization, pain reduction, and patient satisfaction can improve, but surgery does not guarantee an optimal result: Patients and surgeons report being dissatisfied with the results. Consensus is that conservative treatment is more effective than surgery,[21] particularly since patients have extra risks of surgical complications due to the disease. Three basic surgical problems arise due to 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.[42] If considering surgical intervention, it would be prudent to seek care from a surgeon with extensive knowledge and experience in treating patients with EDS and joint hypermobility issues.[citation needed]

Studies have shown that local anesthetics, arterial catheters and central venous catheters cause a higher risk in haematoma formation in patients with Ehlers–Danlos syndrome. Ehlers–Danlos syndrome patients also show a resistance to local anaesthetics.[46] Resistance to Xylocaine and Bupivacaine is not uncommon, and Carbocaine tends to work better in EDS patents. Special recommendations for anesthesia in EDS patients are prepared by orphan anesthesia.eu and deal with all aspects of anesthesia for EDS patients.[47] Detailed recommendations for anesthesia and perioperative care of patients with EDS should be used to improve patient safety.[48]

Surgery with Ehlers–Danlos patients requires careful tissue handling and a longer immobilization afterward.[citation needed]

Prognosis[edit]

The outlook for individuals with EDS depends on the type of EDS they have. Symptoms vary in severity, even within one sub-type, and the frequency of complications changes individually. Some people have negligible symptoms while others are severely restricted in their 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 Hypermobility-type than in Classical-type or Vascular-type.[citation needed]

Although all types are potentially life-threatening, the majority of individuals will have a normal lifespan. However, those with blood vessel fragility have a high risk of fatal complications. Arterial rupture is the most common cause of sudden death in EDS. Spontaneous arterial rupture most often occurs in the second or third decade, but can occur at any time. The median life-expectancy in the population with Vascular EDS is 48 years.[49]

Epidemiology[edit]

Ehlers–Danlos syndrome is an inherited disorder estimated to occur in about 1 in 5,000 births worldwide. Initially, prevalence estimates ranged from 1 in 250,000 to 1 in 500,000 people, but these estimates were soon found to be vastly inaccurate as the disorder received further study and medical professionals became more adept at accurately diagnosing EDS. In fact, many experts now believe that Ehlers–Danlos syndrome may be far more common than the currently accepted estimate due to the wide range of severities with which the disorder presents.[50]

The prevalence of the six types differs dramatically. The most commonly occurring is the Hypermobility type, followed by the Classical type. The other types of Ehlers–Danlos syndrome are very rare. For example, fewer than ten infants and children with the dermatosparaxis type have been described worldwide. Some types of Ehlers–Danlos are more common in Ashkenazi Jews. For example, the chance of being a carrier for type-VIIc Ehlers–Danlos is 1 in 248 in Ashkenazi Jews, whereas the prevalence of this mutation in the general population is 1 in 2,000.[51]

Society and culture[edit]

A sideshow performer demonstrating his extreme Ehlers–Danlos syndrome
  • In the 19th century, there were several sideshow performers 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.[52]
  • Several current celebrities have EDS:
    • Actress Cherylee Houston has hypermobile EDS and uses a wheelchair; she was the first full-time disabled actress on Coronation Street.[53]
    • The condition may have contributed to the virtuoso violinist Niccolò Paganini's skill as he was able to play wider fingerings than the normal violinist.[54]
    • Science blogger Yvette d'Entremont aka Science Babe has Ehlers–Danlos syndrome.[55]
    • Adult film star Mandy Morbid has discussed the impact EDS has on her mobility and her life.[56]
    • Rei Haycraft, lead singer for the hard rock band Raimee, artist, and illustrator. Haycraft has created songs and a documentary about living with Ehlers–Danlos, as well as written songs about its impact on her life.[57][58]
    • American disability rights activist Annie Segarra has EDS, and talks about the condition on her Annie Elainey YouTube channel.[59]
  • The condition is mentioned in the song "Dorsal Horn Concerto" by the British comedy band the Amateur Transplants.[60]
  • The condition has been mentioned in many television shows, including:
    • The subject of the Season 8 premiere of the A&E series Intervention, Linda, claims to have EDS.[61]

Other species[edit]

A dog with Ehlers–Danlos syndrome

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.[citation needed]

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, the disease is being recognized in all age groups and all activity levels. It has even been noted in newborn foals.[citation needed] 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.[62][63]

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