Ehlers–Danlos syndrome

Ehlers–Danlos syndrome
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.
Classification and external resources
Specialty	Medical genetics
ICD-10	Q79.6 (ILDS Q82.817)
ICD-9-CM	756.83
DiseasesDB	4131
MedlinePlus	001468
eMedicine	derm/696 ped/654
Patient UK	Ehlers–Danlos syndrome
MeSH	D004535
Orphanet	98249

Ehlers–Danlos syndrome (EDS) is an inherited connective tissue disorder with different presentations that have been classified into several primary types. EDS is caused by a defect in the structure, production, or processing of collagen or proteins that interact with collagen, such as mutations in the COL5A or COL3A genes. (This is the collagen of granulation tissue, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Commonly associated with keloid formation, reticular fiber, and found in artery walls, skin, intestines and the uterus—COL3A1.) The collagen in connective tissue helps tissues resist deformation. Collagen is an important contributor to the physical strength of skin, joints, muscles, ligaments, blood vessels and visceral organs; abnormal collagen renders these structures more elastic. In some cases, the severity of the mutation can be life-threatening. EDS can have neuromuscular complications including ocular and ophthalmic complications.

There is no cure for EDS, and treatment is supportive, including close monitoring of the digestive, excretory and particularly the cardiovascular systems. Occupational and physical therapy, bracing, and corrective surgery may help with the frequent injuries and pain that tend to develop in certain types of EDS, although extra caution and special practices are advised to prevent permanent damage. EDS is a chronic pain disease, with patients suffering daily.

People with EDS are often misdiagnosed with hypochondriasis, depression, chronic fatigue syndrome, and other conditions because EDS is considered an invisible disability and there is generally poor knowledge about EDS among practitioners. Many sufferers of EDS have psychological difficulties as a result of frustration with the medical system and the socially inconvenient combination of appearing normal while being in severe pain. To deal with these issues, interest groups have tried to raise awareness about EDS among medical professionals.

The features of EDS were first described by Hippocrates in 400 BC. 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.

Classification

In the past, there were 10 recognized types of Ehlers–Danlos syndrome. In 1997, researchers proposed a simpler classification that reduced the number of major types to six and gave them descriptive names. These six major types are listed here. Other types of the condition may exist, but they have been reported only in single families or are not well characterized. Except for hypermobility, 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. Although the classifications are well defined, it is rare for a case to fit neatly in a single category, and cross-over symptoms lead to under-diagnosis or mis-diagnosis. Therefore, patients should not rely on the "fact" of having a certain type of EDS if cross-over symptoms are evident because of possibly life-threatening symptoms. For example, it is possible for an individual with Classical EDS to exhibit symptoms of Hypermobility or Vascular EDS.

In order of prevalence in the population, the classifications are:

Name	Number	Description	OMIM	Gene(s)
Hypermobility	type 3	Affects 1 in 10,000 to 15,000 and is caused by an autosomal dominant or autosomal recessive mechanism. Mutations in either of two separate genes (which are also involved in Vascular EDS and Tenascin-X deficiency EDS, respectively) may lead to this variant. However, there has only been one report involving one family showing this mutation in COL3A1), while there is some thought that the TNXB related EDS is actually its own separate subtype apart from type III. Joint hypermobility is the hallmark of this type, with less severe skin manifestations. Joint instability and chronic musculoskeletal pain are particularly prominent in this type. Patients with the Hypermobility Type experience frequent joint dislocations and subluxations (partial/incomplete dislocations), with or without trauma. As a result, pain is a common, severe, and a lifelong symptom of this type. Additionally, osteoarthritis is common, and many get it earlier in life than expected.	130020	TNXB, SometimesCOL3A1 (see description).
Classical	types 1 & 2	Affects approximately 1 in 20,000 to 50,000 people. It is caused by autosomal dominant mechanism and affects type-V collagen, as well as type-I collagen. Type 1 typically presents with severe skin involvement, and type 2 presents with mild to moderate skin involvement. Patients with the Classical Type may experience the same symptoms as the Hypermobility Type. The main difference between the Hypermobility and Classical Types are the Classical has more skin involvement while the Hypermobility Type has more joint involvement. Those with Classical EDS can also have severe joints issues like those with the Hypermobility Type.	130000, 130010	COL5A1, COL5A2, COL1A1
Vascular	type 4	Is an autosomal dominant defect in the type-III collagen synthesis; affecting approximately 1 in 100,000 to 250,000 people. The vascular type is considered one of the more serious forms of Ehlers–Danlos syndrome because blood vessels and organs are fragile and prone to tearing (rupture). Many patients with EDS type 4 express a characteristic facial appearance (large eyes, small chin, sunken cheeks, thin nose and lips, lobeless ears), have a small stature with a slim build, and typically have thin, pale, translucent skin (veins can usually be seen on the chest and abdomen) with very easy bruising and propensity to develop ecchymoses (bruising without trauma). About one in four people with vascular type EDS develop a significant health problem by age 20 and more than 80 percent develop life-threatening complications by age 40.	130050	COL3A1
Kyphoscoliosis	type 6	Is an autosomal recessive defect due to deficiency of an enzyme called lysyl hydroxylase; it is very rare, with fewer than 60 cases reported. The kyphoscoliosis type is characterised by progressive curvature of the spine (scoliosis), thin conjunctiva with blue appearing sclera (eyes) and severe muscle weakness.	225400, 229200	PLOD1
Arthrochalasia	types 7A & B	Is an autosomal dominant defect which is very rare, with roughly 30 cases reported. It affects type-I collagen. The arthrochalasia type is characterised by very loose joints and dislocations involving both hips. Their joints are much looser than the Hypermobility Type. It could be considered more severe than Hypermobility Type.	130060	COL1A1, COL1A2
Dermatosparaxis	type 7C	Autosomal recessive. Very rare, with approximately 10 cases reported. The dermatosparaxis type is characterized by extremely fragile and sagging skin.	225410	ADAMTS2

Overall, research statistics of EDS show the prevalence as 1 in 2,500 to 1 in 5,000 people. Recent clinical experience suggests that this condition goes under-diagnosed and the condition is more common than these ratios indicate.

Other types

Forms of EDS 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

Signs and symptoms

Individual with EDS displaying hypermobile joints

Individual with EDS displaying skin hyperelasticity

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.

Musculoskeletal

• Hyper-flexible joints (It is possible to be very flexible or have "double joints", however, this is not the same as EDS.)
• Unstable joints that are prone to sprain, dislocation, subluxation and hyperextension
• Thoracic outlet syndrome
• Early onset of advanced osteoarthritis
• Chronic degenerative joint disease
• Swan neck deformity of the fingers
• Boutonniere deformity of the fingers
• Tearing of tendons or muscles
• Deformities of the spine, such as scoliosis (curvature of the spine), kyphosis (a thoracic hump), tethered spinal cord syndrome, occipitoatlantoaxial hypermobility
• Myalgia (muscle pain) and arthralgia (joint pain), which may be severe
• Trendelenburg's sign
• Osgood-Schlatter Disease

Skin

• Fragile skin that tears easily
• Atrophic “cigarette paper” scars

• Easy bruising
• Redundant skin folds
• Molluscoid pseudotumors, especially on pressure points
• Subcutaneous spheroids
• Livedo reticularis

Cardiovascular

• Arterial rupture
• Valvular heart disease (such as mitral valve prolapse, which creates an increased risk for infective endocarditis during surgery, as well as possibly progressing to a life-threatening degree of severity of the prognosis of mitral valve prolapse)
• Dilation and/or rupture of ascending aorta
• Postural orthostatic tachycardia syndrome
• Raynaud's phenomenon
• Varicose veins
• Heart Murmur

Other manifestations or complications

• Hiatial hernia
• Anal prolapse
• Collapsed lung (pneumothorax)
• Nerve compression disorders (carpal tunnel syndrome, acroparesthesia, neuropathy)
• Insensitivity to local anesthetics.
• Arnold–Chiari malformation (brain disorder)
• 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.
• Sleep apnea
• 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 cerebral spinal fluid, leading to issues related to the autonomic nervous system failing to work properly.

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

The pain associated with this condition is a serious complication.

Genetics

As mentioned under "Classification" above, only some variations of Ehlers-Danlos can be positively identified as tied to specific genetic variation (as opposed to epigenetic or environmental factors).

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

• Fibrous proteins: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, and TNXB
• Enzymes: ADAMTS2, PLOD1, B4GALT7, DSE, and D4ST1/CHST14

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 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.

Diagnosis

A diagnosis can be made by an evaluation of medical history and clinical observation. The Brighton 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.

Differential diagnosis

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. 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 unmonitored case of EDS, a correct diagnosis is very important. Pseudoxanthoma elasticum (PXE) is worth consideration in diagnosing a patient.

Management

There is no 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. Orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances, although it is advised that individuals not become dependent on them until there are no other options for mobility. One should avoid activities that cause the joint to lock or overextend.

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.

There are different types of physiotherapy. Aquatic therapy promotes muscular development and coordination. With manual therapy, the joint will be gently mobilized within the range of motion and/or manipulations. Electrotherapy like transcutaneous electrical nerve stimulation reduces local musculoskeletal pain.

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). 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.

In general, medical intervention is limited to symptomatic therapy. Before pregnancy, patients with EDS should have genetic counseling. 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.

Despite all these types of conservative therapy, except bracing, results show that conservative therapy is ineffective in contrast to midcarpal instability in normal patients. L. Rombaut showed that in almost 40% of the cases, conservative therapy has a neutral or even a negative outcome. Conservative therapy may be unsuccessful in controlling instability in the longer term.

Surgery

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.

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, 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.

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 patients also show a resistance to local anaesthetics. Special recommendations for anesthesia in EDS patients are prepared by orphan anesthesia.eu and deal with all aspects of anesthesia for EDS patients. Detailed recommendations for anesthesia and perioperative care of patients with EDS should be used to improve patient safety.

Surgery with Ehlers-Danlos patients requires careful tissue handling and a longer immobilization afterward.

X-ray of a wrist with midcarpal instability

Prognosis

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.

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.

EDS is a lifelong condition. Affected individuals may face social obstacles related to their disease daily. Some people with EDS have reported living with fear of significant and painful ruptures, their condition worsening, becoming unemployed due to physical and emotional burdens, and social stigmatization in general.

Epidemiology

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. 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 10 infants and children with the dermatosparaxis type have been described worldwide. Ehlers–Danlos affects males and females of all racial and ethnic backgrounds, although some types are more common among certain groups than others.

Society and culture

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.
• Several current celebrities have EDS:
  • Actress Cherylee Houston has type 3 EDS and uses a wheelchair; she made history by becoming Coronation Street's first full-time disabled actress.
  • 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.
  • Martina Stawski from the YouTube channel Eatyourkimchi has type 3 EDS and briefly addresses the limitations of her condition on some v-log formatted videos on the channel.
  • Eric Shaun Lynch, aka Eric the Midget and later Eric the Actor, a member of Howard Stern's Wack Pack had Ehlers–Danlos Syndrome Type VII.
  • Adult film star Mandy Morbid has discussed the impact EDS has on her mobility and her life.
  • 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.
• The condition is mentioned in the song "Dorsal Horn Concerto" by the British comedy band the Amateur Transplants.
• The condition has been mentioned in many television shows, including:
  • CSI New York in the Season 1 episode, "Blood, Sweat and Tears."
  • FOX series Bones in the Season 4 episode "The Perfect Pieces in the Purple Pond."
  • House in the episodes "House's Head" (Season 4, Episode 15) and "The Dig (House)" (Season 7, Episode 18).
  • The Law & Order episode "Dignity" (Season 20, Episode 5). In the episode, a third-trimester fetus is diagnosed with the condition and is slated for abortion; shortly later, the doctor who is due to perform the abortion is murdered in church.
  • USA Network series Royal Pains episode "After the Fireworks" (Season 4, Episode 1).
  • The subject of the Season 7 premiere of the A&E series Intervention, Linda, claims to have EDS.
  • The Doctors Cirque du Soleil's "O" episode. In this episode, the doctors discuss flexibility and EDS.

Other animals

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.

Degenerative suspensory ligament desmitis (DSLD) is a similar condition seen in many breeds of horses. Though it was originally notated in the Peruvian Paso and thought to be a condition of overwork and older age, the disease 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.

See also

• Abdominal aortic aneurysm
• Arnold-Chiari malformation
• Joint dislocation
• Dural ectasia
• Dysautonomia
• Gorlin sign
• Hypermobility
• Marfan syndrome
• Mitral valve prolapse
• Postural orthostatic tachycardia syndrome
• Subluxation
• Tethered spinal cord syndrome
• Tricuspid regurgitation
• Wrinkly skin syndrome

External links

• Ehlers–Danlos syndrome at DMOZ
• University of Washington Medicine, Orthopaedics and Sports Medicine Multi-page explanation of EDS, including symptoms, genetics, diagnosis, and treatment
• National Institute of Health on Hypermobility EDS
• Ehlers-Danlos syndrome Genetic Home Reference. Federal Government.
  • Ehlers–Danlos Syndrome, Classic Type. Includes: Ehlers–Danlos Syndrome Type I, Ehlers–Danlos Syndrome Type II
  • GeneReviews/NCBI/NIH/UW entry on Ehlers–Danlos Syndrome Type IV
• eds at NIH/UW GeneTests
• Ehlers–Danlos National Foundation
• Hypermobile – A blog about Ehlers Danlos Syndrome The lack of clinical distinction between the hypermobility type of Ehlers–Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome)
• Management of pain and fatigue in the joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome, hypermobility type): principles and proposal for a multidisciplinary approach
• Anesthesia for EDS patients - Guidelines at orphananesthesia.eu