Ehlers–Danlos syndromes

Ehlers–Danlos syndromes
Individual with an EDS displaying skin hyperelasticity
Specialty Medical genetics, rheumatology
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 Lifelong[3]
Types Hypermobile, classic, vascular, kyphoscoliosis, arthrochalasia, dermatosparaxis, brittle cornea syndrome, others[4]
Causes Genetic[1]
Risk factors Family history[1]
Diagnostic method Genetic testing, skin biopsy[3]
Differential diagnosis Marfan syndrome, cutis laxa syndrome, familial joint hypermobility syndrome[3]
Treatment Supportive[5]
Prognosis Depends on specific disorder[3]
Frequency 1 in 5,000[1]

Ehlers–Danlos syndromes (EDSs) 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.[1][3]

EDSs are due to a mutation in one of more than a dozen different genes.[1] The specific gene affected determines the specific 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]

No cure is known.[5] Treatment is supportive in nature.[3] Physical therapy and bracing may help strengthen muscles and support joints.[3] While some disorders result in a normal life expectancy, those that affect blood vessels generally result in a shorter life expectancy.[5]

EDSs affect about one in 5,000 people globally.[1] The prognosis depends on the specific disorder.[3] Excess mobility was first described by Hippocrates in 400 BC.[6] 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.[7]

Signs and symptoms

Signs vary widely based on the specific EDS the person has. This group of disorders affects connective tissues, most typically in the joints, skin, and blood vessels and causes effects ranging from mildly loose joints to life-threatening complications.[8] Major signs and symptoms are listed below.

Musculoskeletal

Musculoskeletal symptoms include hyperflexible joints that are unstable and prone to sprain, dislocation, subluxation, and hyperextension.[7][9] There can be an early onset of advanced osteoarthritis,[10] chronic degenerative joint disease,[10] swan-neck deformity of the fingers,[11] and Boutonniere deformity of the fingers. Tearing of tendons or muscles may occur.[12] 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.[13] There can also be myalgia (muscle pain) and arthralgia (joint pain),[14] 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.[15] Osgood–Schlatter disease, a painful lump on the knee, is common as well.[16] In infants, walking can be delayed (beyond 18 months of age), and bottom-shuffling instead of crawling occurs.[17]

Skin

The weak connective tissue causes fragile skin that tears easily,[10] atrophic "cigarette paper" scars, and easy bruising.[1][7][18] Redundant skin folds, especially on the eyelids also happen.[10][19] Molluscoid pseudotumors,[20] especially on pressure points. Petechiae,[21] subcutaneous spheroids,[20] livedo reticularis, and piezogenic papules are less common.[22] In vascular EDS, thin, translucent, and extremely fragile skin that tears easily is also a symptom.

Cardiovascular

Other manifestations

Gorlin's sign in a case of EDS

Because it is often undiagnosed or misdiagnosed in childhood, some instances of EDSs have been mischaracterized as child abuse.[40]

The pain associated with the disorders may be severe.[41]

Genetics

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 EDSs can be positively identified as tied to specific genetic variation.

Mutations in these genes can cause EDSs:

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.[1] 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.[42]

Diagnosis

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 multiple individuals in a family are affected, performing prenatal diagnosis may be possible using a DNA information technique known as a linkage study.[43] Knowledge about EDSs among practitioners is poor.[44][45]

Classification

As of 2017, 13 EDSs had been characterized, with a significant overlap in features.[4]

Hypermobile EDS (type 3 hEDS) is 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.[4] The mutation that causes this type of EDS is unknown. Less skin involvement is seen than other types. No genetic test for this type is available.

Classical EDS (type 1 cEDS) is 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.[4] The mutation that causes this type of EDS is in the genes COL5A1, COL5A2, and COL1A1. It involves the skin more than hEDS.

Vascular EDS (type 4 vEDS) is 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, and 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.[46] 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.[4] Is can be caused by the mutations in the COL3A1 gene.

Kyphoscoliosis EDS (type 6 kEDS) is 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).[4] It can be caused by mutations in the gene PLOD1.

Arthrochalasia EDS (types 7A & B aEDS) 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.[4] 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 (type 7C dEDS) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; and hernias. It is extremely rare, with around 10 cases reported.

Brittle cornea syndrome is characterized by thin corneaa, early-onset progressive keratoglobus or keratoconus, and blue sclerae.[4] Classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often.[47]

Classical-like EDS (type 1 cEDS) 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).[4]

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.[4]

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.[4]

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).[4]

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.[4]

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).[4]

History

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.[48]

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:

  • 305200 – type 5
  • 130080 – type 8 – unspecified gene, locus 12p13
  • 225310 – type 10 – unspecified gene, locus 2q34
  • 608763 – Beasley–Cohen type
  • 130070 – progeroid form – B4GALT7
  • 606408 – due to Tenascin-X deficiency – TNXB
  • 130090 – type unspecified
  • 601776 – D4ST1-deficient Ehlers–Danlos syndrome (adducted thumb-clubfoot syndrome) CHST14

Differential diagnosis

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.[49]

In the past, Menkes disease, a copper metabolism disorder, was thought to be an EDS. Patients 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.[50] Pseudoxanthoma elasticum (PXE) is worth consideration in diagnosis.[51]

Management

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. Patients should avoid activities that cause the joint to lock or overextend.[52]

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.[53][54]

Aquatic therapy promotes muscular development and coordination.[55] With manual therapy, the joint is gently mobilized within the range of motion and/or manipulations.[53][54] 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 patients have responded to vitamin C.[56] Special precautions are often taken by medical care workers because of the sheer number of complications that tend to arise in EDS patients. In vascular EDSs, signs of chest or abdominal pain are considered trauma situations.[57]

In general, medical intervention is limited to symptomatic therapy. Before pregnancy, patients 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 patients 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.[58]

Surgery

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.[53]

Common surgical procedures are joint debridement, tendon replacements, capsulorraphy, and arthroplasty. After surgery, the 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,[25] particularly since patients 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.[53] 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 in haematoma formation in people with an EDS. People with EDSs also show a resistance to local anaesthetics.[59] 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.[60] Detailed recommendations for anesthesia and perioperative care of people with an EDS should be used to improve safety.[61]

Surgery in people with an EDS requires careful tissue handling and a longer immobilization afterward.

Prognosis

The outlook for individuals with an EDS depends on the specific 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 patients 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.[62]

Epidemiology

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 the disorders received further study 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.[63]

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.[64]

Society and culture

Gary "Stretch" Turner showing his extreme Ehlers Danlos syndrome
  • In the 19th century, several sideshow performers 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.[65]
  • Several current celebrities have an EDS:
    • Actress Cherylee Houston has hypermobile EDS and uses a wheelchair; she was the first full-time disabled actress on Coronation Street.[66]
    • An EDS may have contributed to the virtuoso violinist Niccolò Paganini's skill, as he was able to play wider fingerings than the normal violinist.[67]
    • Science blogger Yvette d'Entremont (the Science Babe) has an EDS.[68]
    • Adult film star Mandy Morbid has discussed the impact her EDS has on her mobility and her life.[69]
    • Rei Haycraft, lead singer for the hard rock band Raimee, artist, and illustrator, has created songs and a documentary about living with an EDS, as well as written songs about its impact on her life.[70][71]
    • American disability-rights activist Annie Segarra has an EDS, and talks about the condition on her Annie Elainey YouTube channel.[72]
    • Eric "The Actor" Lynch, frequent caller to The Howard Stern Show, had arthrochalasia EDS, resulting in his mangled fingers.[73]
    • Singer Mandy Harvey gradually lost her hearing as a result of a disorder; by the time she was 19, she was legally deaf. Ten years later, at age 29, she competed in America's Got Talent, season 12, finishing in fourth place.[74][75]
    • Contortionist Daniel Browning Smith has hypermobile EDS and holds the current Guinness World Record for the most flexible man as of 2018.
    • Gary "Stretch" Turner (shown right), a sideshow performer in the Circus Of Horrors, has an extreme form of EDS. He holds the current Guinness World Record for most elastic skin with 6 inches.
  • The condition has been mentioned in many television shows, including:
    • The subject of the season-eight premiere of the A&E series Intervention, Linda, claims to have an EDS.[76]
    • In season 13, episode four of Grey's Anatomy, a patient is diagnosed with an EDS.[77]

Other species

Ehlers–Danlos-like syndromes have been shown to be hereditary in Himalayan cats, some domestic shorthair cats,[78] and in certain breeds of cattle.[79] It is seen as a sporadic condition in domestic dogs.

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.[80][81]

References

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