Ehlers-Danlos Syndrome (EDS) (also known as "Cutis hyperelastica"[1]) is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen (a protein in connective tissue). Connective tissue helps support the skin, muscles, ligaments and organs of the body. Depending on the individual mutation, the severity of the syndrome can vary from mild to life-threatening. There is no known cure. Treatment is supportive.
The syndrome is named after two doctors, Edvard Ehlers of Denmark, and Henri-Alexandre Danlos of France, who identified it at the turn of the 20th century.
Symptoms vary widely based on which type of EDS the patient has. In each case, however, the symptoms are ultimately due to faulty or reduced amounts of Type III collagen. EDS most typically affects the joints, skin, and blood vessels, with symptoms such as loose, overly-flexible joints; smooth or stretchy, easily-bruised skin; abnormal wound healing and scar formation; and small, fragile blood vessels. All forms of EDS affect the joints, causing hypermobility, or joints that extend beyond the normal range of motion. [3] As a result of their hypermobility, individuals with EDS are more susceptible to injuries such as: dislocations, subluxations, sprains, strains, and sometimes fractures. Because it is often undiagnosed, some instances of Ehlers-Danlos syndrome have been mischaracterized as child abuse
There are 6 types of Ehlers Danlos Syndrome.
Hypermobility type
Former type 3, Hypermobility EDS affects 1 in 10,000 to 15,000 individuals, making it the most common variant of the disease. Signs and symptoms may go unrecognized by medical practitioners until complications occur. It is caused by an autosomal dominant 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. Diagnosis is made primarily on clinical observations. The major signs and symptoms include:
Loose, unstable joints that are prone to: sprains, dislocations, subluxations (partial dislocations), hyperextension (double jointedness)
Flat feet
High and narrow palate, usually resulting in dental crowding
Easy bruising
Velvety-smooth skin, which may be mildly stretchy
Muscle weakness, often made worse by cold weather
Early onset of osteoarthritis (usually develops in mid-30s)
Cardiac effects: some degree of Dysautonomia or 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) [6]
Other, less common symptoms and complications can include:
Osteopenia (low bone density)
Deformities of the spine, such as: Scoliosis (curvature of the spine), Kyphosis (a thoracic hump), Tethered spinal cord syndrome, Basilar invagination (cranial settling), Arnold-Chiari malformation [7]
Functional bowel disorders (functional gastritis, irritable bowel syndrome)
Increased nerve compression disorders (carpal tunnel syndrome, acroparesthesia, neuropathy)
Vascular skin conditions: Raynaud's phenomenon, Livedo reticularis
Fibromyalgia symptoms: Myalgia and arthralgia
otosclerosis (hearing loss) [8]
Premature rupture of membranes during pregnancy
Infants with hypermobile joints often appear to have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking
The pain associated with this condition is a serious complication.
Classical type
Under the old classification system, EDS classical type was divided into two separate types: type I (severe) and type II (minor). It affects approximately 2 to 5 in 100,000 people, making it the second most common type of EDS. It affects type-V collagen, as well as type I. The major symptoms involved in EDS classical type are the skin and joints. Affected individuals typically have:
skin that is smooth and extremely stretchy and bruises easily
extensive scarring or unusually wide scars, particularly at the knees, elbows, forehead, and chin
joints are hyperextensible, giving a tendency towards dislocations, sprains, and subluxations (most commonly in the shoulder, patella, metacarpophalangeal joint, and temporomandibular joint)
Due to decreased muscle tone, affected infants may experience a delay in reaching motor milestones
Children may have a tendency to develop hernias or other organ shifts within the abdomen
At this time there is no definitive test for the diagnosis of classical EDS. Both DNA and biochemical studies have been used to help identify affected individuals. In some cases, a skin biopsy has been found to be useful in confirming a diagnosis. Unfortunately, these tests are not sensitive enough to identify all individuals with classical EDS. 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.
Vascular type
Is an autosomal dominant defect in the type-III collagen synthesis; affecting approximately 1 in 100,000 people. Formerly called EDS type IV, EDS vascular type is the most severe form. Past studies have placed life expectancy at around 48 years. However, that number is likely skewed based on the fact that the disease is (as are all EDS types) vastly underdiagnosed, leading to a misleading proportion of people diagnosed being those diagnosed upon death. Increased awareness among physicians (and the public) will help make this number more accurate and bring down the overall number of premature deaths. Signs and symptoms include:
Hypermobility that is most apparent in the fingers or toes
delicate skin is joined by fragile blood vessel walls and organ membranes, with a tendency to rupture or develop aneurysms.
Patients typically have thin, pale, translucent skin (veins can usually be seen on chest)
Arterial/intestinal/uterine fragility or rupture
extensive bruising
some patients express the characteristic facial appearance (large eyes, small chin, thin nose and lips, lobeless ears) and have a small stature
Due to possibility of uterine rupture, pregnancy can be life-threatening in people with this variant. EDS vascular type is caused by a change in the gene COL3A1, which codes for one of the collagen chains used to build Collage type III. Laboratory testing is available for this form of EDS. A skin biopsy may be used to demonstrate the structurally abnormal collagen. This type of biochemical test identifies more than 95% of individuals with EDS vascular type. Laboratory testing is recommended for individuals with two or more of the major criteria. DNA analysis may also be used to identify the change within the COL3A1 gene. This information may be helpful for genetic counseling purposes. Prenatal testing is available for pregnancies in which an affected parent has been identified and their DNA mutation is known or their biochemical defect has been demonstrated.
Kyphoscoliosis type
It is very rare, with fewer than 60 cases reported. The major symptoms of kyphoscoliosis type, formerly called EDS type VI, are general joint looseness. At birth, the muscle tone is poor, and motor skill development is subsequently delayed. Also, infants with this type of EDS have an abnormal curvature of the spine (scoliosis). The scoliosis becomes progressively worse with age, with affected individuals usually unable to walk by age 20. The eyes and skin are fragile and easily damaged, and blood vessel involvement is a possibility. The bones may also be affected as demonstrated by a decrease in bone mass. Kyphoscoliosis type is inherited in an autosomal dominant manner. There are four major clinical diagnostic criteria for EDS kyphoscoliosis type. These include generally loose joints, low muscle tone at birth, scoliosis at birth (which worsens with age), and a fragility of the eyes, which may give the white area of the eye a blue tint or cause the eye to rupture. This form of EDS is caused by a change in the PLOD gene on chromosome 1, which encodes the enzyme lysyl hydroxylase. A laboratory test is available in which urinary hydroxylysyl pryridinoline is measured. This test, performed on urine is extremely sensitive and specific for EDS kyphoscolios type. Laboratory testing is recommended for infants with three or more of the major diagnostic criteria. Prenatal testing is available if a pregnancy is known to be at risk and an identified affected family member has had positive laboratory testing. An amniocentesis may be performed in which fetal cells are removed from the amniotic fluid and enzyme activity is measured.
Arthrochalasia type
Is also very rare, with about 30 cases reported. Formerly called EDS type VII, the distinguishing feature is congenital hip dislocation. Severe joint hypermobility with recurrent dislocations and subluxations are common, which may lead to early and/or severe osteoarthritis. Skin hyperextensibility, easy bruising, tissue fragility, atrophic scars, loss of muscle tone, Kyphoscoliosis, and osteopenia (bones which are less dense than normal) are also possible clinical manifestations. Arthrochalasia type is inherited in an autosomal dominant manner. There are two major clinical diagnostic criteria for EDS arthrochalasia type. These include sever generalized joint hypermobility and bilateral hip dislocation present at birth. This form of EDS is caused by a change in either of two components of Collage type I, called proa1(I) type A and proa2(I) type B. A skin biopsy may be performed to demonstrate an abnormality in either components. Direct DNA testing is also available.
Dermatosparaxis type
Also very rare, with about 10 cases reported. Individuals with this type of EDS, once called type VIIC, have extremely fragile skin that bruises easily but does not scar excessively. The skin is soft and may sag, leading to an aged appearance even in young adults. Joints are loose and unstable. Individuals may also experience hernias. Dermatosparaxis type is inherited in an autosomal dominant manner. There are two major clinical diagnostic criteria for EDS dematosparaxis type. These include severe skin fragility and sagging or aged appearing skin. This form of EDS is caused by a change in the enzyme called procollagen I N-terminal peptidase. A skin biopsy may be preformed for a definitive diagnosis of Dermatosparaxis type.
Other types
While the above symptomatology is clean and defined, the disease itself rarely obeys these neat categorizations. Cross-over symptoms for all types are prevalent and lead to under-diagnosis or mis-diagnosis. No patient should assume or rely on the "fact" they have a certain type of EDS when cross-over symptoms are evident and can be life-threatening.
"The large number of distinct types of the Ehlers-Danlos syndrome that have already been identified indicates great heterogeneity, but clearly that heterogeneity is not exhausted by the present classification." Forms of EDS within 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 within this group include X-linked dominant, autosomal dominant, and autosomal dominant.
Treatment/management
There is no known cure for Ehlers Danlos Syndrome. The treatment is supportive. Physical therapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing) may be helpful. One should avoid activities that cause the joint to lock or overextend.
A physician may prescribe bracing to stabilize joints. Surgical repair of joints may be necessary at some time. 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. To decrease bruising and improve wound healing, some patients have responded to ascorbic acid (vitamin C) by taking 1 to 4 grams daily. Prior to starting a regimen such as this, it is imperative to consult with your physician for specific recommendations.
In general, medical intervention is limited to symptomatic therapy. Prior to 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. Family members, teachers and friends should be provided with information about EDS so they can accept and assist the child as necessary.
Prognosis
The outlook for individuals with EDS depends on the type of EDS with which they have been diagnosed. Symptoms vary in severity, even within one sub-type, and the frequency of complications changes on an individual basis. Some individuals have negligible symptoms while others are severely restricted in their daily life. Extreme joint instability, pain, and spinal deformities may limit a person's mobility. Most individuals will have a normal lifespan. However, those with blood vessel involvement have an increased risk of fatal complications.
EDS is a lifelong condition. Affected individuals may face social obstacles related to their disease on a daily basis. Some people with EDS have reported living with fears of significant and painful ruptures, becoming pregnant, their condition worsening, becoming unemployed due to physical and emotional burdens, and social stigmatization in general.
Similar disorders
There are several disorders that have some of the characteristics of 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. In the past, Menkes disease, a copper metabolism disorder, was thought to be a form of Ehlers-Danlos syndrome. Because of these similar disorders, a correct diagnosis is very important. |
