Ehlers-Danlos syndrome

Definition

The Ehlers-Danlos syndromes (EDS) refer to a group of inherited disorders that affect collagen structure and function. Genetic abnormalities in the manufacturing of collagen within the body affect connective tissues, causing them to be abnormally weak.

Description

Collagen is a strong, fibrous protein that lends strength and elasticity to connective tissues such as the skin, tendons, organ walls, cartilage, and blood vessels. Each of these connective tissues requires collagen tailored to meet its specific purposes. The many roles of collagen are reflected in the number of genes dedicated to its production. There are at least 28 genes in humans that encode at least 19 different types of collagen. Mutations in these genes can affect basic construction as well as the fine-tuned processing of the collagen.

EDS was originally described by Dr. Van Meekeren in 1682. Dr. Ehlers and Dr. Danlos further characterized the disease in 1901 and 1908, respectively. Today, according to the Ehlers-Danlos National Foundation, one in 5, 000 to one in 10, 000 people are affected by some form of EDS.

EDS is a group of genetic disorders that usually affects the skin, ligaments, joints, and blood vessels. Classification of EDS types was revised in 1997. The new classification involves categorizing the different forms of EDS into six major sub-types, including classical, hypermobility, vascular, kyphoscoliosis, arthrochalasia, and dermatosparaxis, and a collection of rare or poorly defined varieties. This new classification is simpler and based more on descriptions of the actual symptoms.

Under the old classification system, EDS classical type was divided into two separate types: type I and typeII. The major symptoms involved in EDS classical type are the skin and joints. The skin has a smooth, velvety texture and bruises easily. Affected individuals typically have extensive scaring, particularly at the knees, elbows, forehead, and chin. The joints are hyperextensible, giving a tendency towards dislocation of the hip, shoulder, elbow, knee, or clavicle. 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. Sprains and partial or complete joint dilocations are also common. Symptoms can range from mild to severe. EDS classical type is inherited in an autosomal dominant manner.

There are three major clinical diagnostic criteria for EDS classical type. These include skin hyperextensibility, unusually wide scars, and joint hypermobility. 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.

Excessively loose joints are the hallmark of this EDS type, formerly known as EDS type III. Both large joints, such as the elbows and knees, and small joints, such as toes and fingers, are affected. Partial and total joint dislocations are common, and particularly involve the jaw, knee, and shoulder. Many individuals experience chronic limb and joint pain, although x rays of these joints appear normal. The skin may also bruise easily. Osteoarthritis is a common occurrence in adults. EDS hypermobility type is inherited in an autosomal dominant manner.

There are two major clinical diagnostic criteria for EDS hypermobility type. These include skin involvement (either hyperextensible skin or smooth and velvety skin) and generalized joint hypermobility. At this time there is no test for this form of EDS.

Formerly called EDS type IV, EDS vascular type is the most severe form. The connective tissue in the intestines, arteries, uterus, and other hollow organs may be unusually weak, leading to organ or blood vessel rupture. Such ruptures are most likely between ages 20 and 40, although they can occur any time, and may be life-threatening.

There is a classic facial appearance associated with EDS vascular type. Affected individuals tend to have large eyes, a thin pinched nose, thin lips, and a slim body. The skin is thin and translucent, with veins dramatically visible, particularly across the chest.

The large joints have normal stability, but small joints in the hands and feet are loose, showing hyperextensibility. The skin bruises easily. Other complications may include collapsed lungs, premature aging of the skin on the hands and feet, and ruptured arteries and veins. After surgery there tends to be poor wound healing, a complication that tends to be frequent and severe. Pregnancy also carries the risk complications. During and after pregnancy there is an increased risk of the uterus rupturing and of arterial bleeding. Due to the severe complications associated with EDS type IV, death usually occurs before the fifth decade. A study of 419 individuals with EDS vascular type, completed in 2000, found that the median survival rate was 48 years, with a range of six to 73 years. EDS vascular type is inherited in an autosomal dominant manner.

There are four major clinical diagnostic criteria for EDS vascular type. These include thin translucent skin, arterial/intestinal/uterine fragility or rupture, extensive bruising, and characteristic facial appearance. 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 als 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.

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 recessive manner.

There are four major clinical diagnostic criteria for EDS kyphoscoliosis type. These include generaly 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 senstive 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.

Dislocation of the hip joint typically accompanies arthrochalasia type EDS, formerly called EDS type VIIB. Other joints are also unusually loose, leading to recurrent partial and total dislocations. The skin has a high degree of stretchability and bruises easily. Individuals with this

type of EDS may also experience mildly diminished bone mass, scoliosis, and poor muscle tone. Arthrochalasia type is inherited in an autosomal dominant manner.

There are two major clinical diagnostic criteria for EDS arthrochalasia type. These include sever generalized joing 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 preformed to demonstrate an abnormality in either components. Direct DNA testing is also available.

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. Individuals may also experience hernias. Dermatosparaxis type is inherited in an autosomal recessive 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.

There are several other forms of EDS that have not been as clearly defined as the aforementioned types. 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 recessive, autosomal dominant, and autosomal recessive.

— Java O. Solis, MS

A congenital or familial disorder characterized by fragility of the skin and blood vessels, hyperlaxity of the joints, hyperelasticity of the skin, subcutaneous pseudotumors, and tendency to hemorrhage postoperatively.

Definition

The Ehlers-Danlos syndrome (EDS) refers to a group of inherited disorders that affect collagen structure and function. Genetic abnormalities in the manufacturing of collagen within the body affect connective tissues, causing them to be abnormally weak. Ehlers-Danlos syndrome is also referred to as inherited connective tissue disorder.

Description

Collagen is a strong, fibrous protein that lends strength and elasticity to connective tissues such as the skin, tendons, organ walls, cartilage, and blood vessels. Each of these connective tissues requires collagen tailored to meet its specific purposes. The many roles of collagen are reflected in the number of genes dedicated to its production. There are at least 28 genes in humans that encode at least 19 different types of collagen. Mutations in these genes can affect basic construction as well as the fine-tuned processing of the collagen.

EDS is a group of inherited connective tissue disorders that usually affects the skin, ligaments, joints, and blood vessels. Classification of EDS types was revised in 1997. The new classification involves categorizing the different forms of EDS into six major sub-types, including classical, hypermobility, vascular, kyphoscoliosis, arthrochalasia, and dermatosparaxis, and a collection of rare or poorly defined varieties. This new classification is simpler than the previous classification system and is primarily based on descriptions of the actual symptoms.

Classical Type

Under the old classification system, EDS classical type was divided into two separate types: type I and type II. The major symptoms associated with EDS classical type involve the skin and joints. The skin has a smooth, velvety texture, and bruises easily. Affected individuals typically have extensive scarring, particularly at the knees, elbows, forehead, and chin. The joints are hyperextensible, giving a tendency toward dislocation of the hip, shoulder, elbow, knee, or clavicle. 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. Sprains and partial or complete joint dislocations are also common. Symptoms can range from mild to severe. EDS classical type is inherited in an autosomal dominant manner.

There are three major clinical diagnostic criteria for EDS classical type: skin hyperextensibility, unusually wide scars, and joint hypermobility. 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, skin biopsy has been found 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.

Hypermobility Type

Excessively loose joints are the hallmark of this EDS type, formerly known as EDS type III. Both large joints, such as the elbows and knees, and small joints, such as toes and fingers, are affected. Partial and total joint dislocations are common, particularly involving the jaw, knee, and shoulder. Many individuals experience chronic limb and joint pain, although x rays of these joints appear normal. The skin may also bruise easily. Osteoarthritis is a common occurrence in adults. EDS hypermobility type is inherited in an autosomal dominant manner.

There are two major clinical diagnostic criteria for EDS hypermobility type. These include skin involvement (either hyperextensible skin or smooth and velvety skin) and generalized joint hypermobility. There is no test for this form of EDS.

Vascular Type

Formerly called EDS type IV, EDS vascular type is the most severe form. The connective tissue in the intestines, arteries, uterus, and other hollow organs may be unusually weak, leading to organ or blood vessel rupture. Such ruptures most likely occur between ages 20 and 40, although they can occur any time, and may be life-threatening.

There is a classic facial appearance associated with EDS vascular type. Affected individuals tend to have large eyes, a thin pinched nose, thin lips, and a slim body. The skin is thin and translucent, with veins dramatically visible, particularly across the chest.

The large joints have normal stability, but small joints in the hands and feet are loose, showing hyperextensibility. The skin bruises easily. Other complications may include collapsed lungs, premature aging of the skin on the hands and feet, and ruptured arteries and veins. After surgery, there may be poor wound healing, a complication that tends to be frequent and severe. Pregnancy also carries the risk of complications. During and after pregnancy, there is an increased risk of the uterus rupturing and of arterial bleeding. Due to the severe complications associated with EDS type IV, death usually occurs before the fifth decade. A study of 419 individuals with EDS vascular type, completed in 2000, found that the median survival rate was 48 years, with a range of six to 73 years. EDS vascular type is inherited in an autosomal dominant manner.

There are four major clinical diagnostic criteria for EDS vascular type. These include thin translucent skin, arterial/intestinal/uterine fragility or rupture, extensive bruising, and characteristic facial appearance. EDS vascular type is caused by a change in the gene COL3A1, which codes for one of the collagen chains used to build Collagen 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 percent 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 the DNA mutation is known or the biochemical defect has been demonstrated.

Kyphoscoliosis Type

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; affected individuals are 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 recessive 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

Dislocation of the hip joint typically accompanies arthrochalasia type EDS, formerly called EDS type VIIB. Other joints are also unusually loose, leading to recurrent partial and total dislocations. The skin has a high degree of stretchability and bruises easily. Individuals with this type of EDS may experience mildly diminished bone mass, scoliosis, and poor muscle tone. Arthrochalasia type is inherited in an autosomal dominant manner.

There are two major clinical diagnostic criteria for EDS arthrochalasia type. These include severe 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 Collagen type I, called proa1(I) type A and proa2(I) type B. A skin biopsy may be performed to demonstrate an abnormality in either component. Direct DNA testing is also available.

Dermatosparaxis Type

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. Individuals may also have hernias. Dermatosparaxis type is inherited in an autosomal recessive 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 performed for a definitive diagnosis of dermatosparaxis type.

Other Types

There are several other forms of EDS that have not been as clearly defined as the aforementioned types. Symptoms of EDS within this category may include 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 recessive, autosomal dominant, and autosomal recessive.

Demographics

EDS was originally described by Dr. Van Meekeren in 1682. Dr. Ehlers and Dr. Danlos further characterized the disease in 1901 and 1908, respectively. According to the Ehlers-Danlos National Foundation, one in 5,000 to one in 10,000 people are affected by some form of EDS.

Causes and Symptoms

There are numerous types of EDS, all caused by changes in one of several genes. The manner in which EDS is inherited depends on the specific gene involved. There are three patterns of inheritance for EDS: autosomal dominant, autosomal recessive, and X-linked (extremely rare).

Chromosomes are made up of hundreds of small units known as genes, which contain the genetic material necessary for an individual to develop and function. Humans have 46 chromosomes, which are matched into 23 pairs. Because chromosomes are inherited in pairs, each individual receives two copies of each chromosome and likewise two copies of each gene.

Changes or mutations in genes can cause genetic diseases in several different ways, many of which are represented within the spectrum of EDS. In autosomal dominant EDS, only one copy of a specific gene must be changed for a person to have EDS. In autosomal recessive EDS, both copies of a specific gene must be changed for a person to have EDS. If only one copy of an autosomal recessive EDS gene is changed, the person is referred to as a carrier, meaning he or she does not have any signs or symptoms of the disease itself, but carries the possibility of passing the disorder to a future child. In X-linked EDS, a specific gene on the X chromosome must be changed. However, this affects males and females differently because males and females have a different number of X chromosomes.

The few X-linked forms of EDS fall under the category of X-linked recessive. As with autosomal recessive, this implies that both copies of a specific gene must be changed for a person to be affected. However, because males only have one X-chromosome, they are affected if an X-linked recessive EDS gene is changed on their single X-chromosome. That is, they are affected even though they have only one changed copy. On the other hand, that same gene must be changed on both of the X-chromosomes in a female for her to be affected.

Although there is much information regarding the changes in genes that cause EDS and their various inheritance patterns, the exact gene mutation for all types of EDS is not known.

When to Call the Doctor

The doctor should be called if a child has symptoms of Ehlers-Danlos syndrome. Medical advice should also be sought if a person has a family history of Ehlers-Danlos syndrome and is planning to conceive a child.

Diagnosis

Clinical symptoms such as extreme joint looseness and unusual skin qualities, along with family history, can lead to a diagnosis of EDS. Specific tests, such as skin biopsies, are available for diagnosis of certain types of EDS, including vascular, arthrochalasia, and dermatosparaxis types. A skin biopsy involves removing a small sample of skin and examining its microscopic structure. A urine test is available for the kyphoscoliosis type.

Treatment

Medical therapy relies on managing symptoms and trying to prevent further complications. There is no cure for EDS.

Braces may be prescribed to stabilize joints, although surgery is sometimes necessary to repair joint damage caused by repeated dislocations. Physical therapy teaches individuals how to strengthen muscles around joints and may help to prevent or limit damage. Elective surgery is discouraged due to the high possibility of complications.

There are anecdotal reports that large daily doses (0.04–0.14 oz, or 1–4 g) of vitamin C may help decrease bruising and aid in wound healing. Constitutional homeopathic treatment may be helpful in maintaining optimal health in persons with a diagnosis of EDS. Before beginning these types of therapies, an individual with EDS should discuss them with his or her doctor. Therapy that does not require medical consultation involves protecting the skin with sunscreen and avoiding activities that place stress on the joints. Wounds and infections must be treated with care because tissue healing may be poor. Suturing can be difficult, for the skin can be extremely fragile.

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. Some individuals have negligible symptoms, while others are severely restricted in their daily life. Extreme joint instability and scoliosis may limit a person's mobility. Most individuals will have a normal lifespan. However, those with blood vessel involvement, particularly persons with EDS vascular type, 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 individuals with EDS have reported living with fears of significant and painful skin ruptures, becoming pregnant (especially those with EDS vascular type), experiencing worsening of their condition, becoming unemployed due to physical and emotional burdens, and undergoing social stigmatization in general.

Some people with EDS are not diagnosed until well into adulthood and, in the case of EDS vascular type, occasionally not until after death due to complications of the disorder. The diagnosis may be devastating to the individual and, in many cases, to other family members when they learn they are at risk for being affected.

Although children with EDS face significant challenges, it is important to remember that each child is unique with his or her own distinguished qualities and potential. Persons with EDS go on to have families and careers, and to be respected citizens, surmounting the challenges of their disease.

Prevention

If a couple has had a child diagnosed with EDS, the chance that they will have another child with the same disorder depends on the form of EDS the child has and if either parent is affected by the same disease.

In classical autosomal dominant EDS, the risk for recurrence in the parents' other children is one in four.

X-linked recessive EDS is accompanied by a slightly more complicated pattern of inheritance. If a father with an X-linked recessive form of EDS passes a copy of his X chromosome to his children, the sons will be unaffected and the daughters will be carriers. If a mother is a carrier for an X-linked recessive form of EDS, she may have affected or unaffected sons, or carrier or unaffected daughters, depending on the second sex chromosome inherited from the father.

Prenatal diagnosis is available for specific forms of EDS, including kyphosocliosis type and vascular type. However, prenatal testing is only a possibility in these types if the underlying defect has been found in another family member.

Parental Concerns

Constant bruises, skin wounds, and trips to the hospital take their toll on affected children and their parents. Prior to diagnosis, parents of children with EDS have found themselves under suspicion of child abuse.

Management of all types of EDS may include genetic counseling to help the affected individual and his or her family understand the disorder and its impact on other family members and future children.

Resources

Books

Icon Health Publications. Ehlers-Danlos Syndrome: A Medical Dictionary, Bibliography, and Annotated Research Guide to the Internet. San Diego, CA: Icon Health Publications, 2004.

——. The Official Patient's Sourcebook on Ehlers-Danlos Syndrome: A Revised and Updated Directory for the Internet Age. San Diego, CA: Icon Health Publications, 2002.

Massoud, Lindalee. Ehlers-Danlos Syndrome: Medical and Practical Information. Flint, MI: SignQuest Publishers, 1997.

PM Medical Health News. 21st Century Complete Guide to Ehlers-Danlos Syndrome (EDS), Connective Tissue Disorders, Hypermobility, Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians. Washington, DC: Progressive Management, 2004.

Periodicals

"Living a Restricted Life with Ehlers-Danlos Syndrome." International Journal of Nursing Studies 37 (2000): 111–118.

Organizations

Ehlers-Danlos Support Group - UK. P.O. Box 335, Farnham, Surrey, GU10 1XJ. UK. +44 1252 690 940. Web site: www.ehlers-danlos.org.

Ehlers-Danlos National Foundation. 6399 Wilshire Blvd., Ste. 203, Los Angeles, CA 90048 (323) 651-3038. Fax: (323) 651-1366. Web site: www.ednf.org.

Web Sites

GeneClinics. Available online at: www.geneclinics.org.

[Article by: Judith Sims Java O. Solis, M.S.]

A congenital hereditary syndrome of joint hyperextensibility, hyperelasticity and fragility of the skin, poor wound healing leaving parchment-like scars, capillary fragility and subcutaneous nodules after trauma. Called also cutis hyperelastica, cutaneous asthenia, hereditary collagen dysplasia.
In humans a series of these disorders, listed as Ehlers–Danlos syndrome Type I to Type VII, represent different errors in collagen synthesis and maintenance with subsequent variations in clinical and pathological manifestations.

Ehlers-Danlos Syndrome
Classification and external resources
ICD-10	Q79.6
ICD-9	756.83
MedlinePlus	001468
eMedicine	derm/696 ped/654
MeSH	D004535

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). The collagen in connective tissue helps tissues to resist deformation (increases its elasticity). In the skin, muscles, ligaments, blood vessels, and visceral organs collagen plays a very significant role and with reduced elasticity, secondary to abnormal collagen, pathology results. Depending on the individual mutation, the severity of the syndrome can vary from mild to life-threatening. There is no cure and treatment is supportive, including close monitoring of cardiovascular system.

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. ^[2]

Contents 1 Symptoms 2 Classification 2.1 Other types 3 Genetics 4 Diagnosis 5 Epidemiology 6 Treatment/management 7 Prognosis 8 Similar disorders 9 EDS-like symptoms in animals 10 Pop culture 11 See also 12 References 13 External links

Symptoms

Individual with EDS displaying hypermobile joints.

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, the major signs and symptoms include:

• Highly flexible fingers and toes
• Loose, unstable joints that are prone to: sprains, dislocations, subluxations (partial dislocations), hyperextension (double jointedness) ^[3]
• Flat feet
• High and narrow palate, resulting in dental crowding
• Easy bruising
• Fragile blood vessels resulting from cystic medial necrosis with tendency towards aneurysm (even abdominal aortic aneurysm)
• Velvety-smooth skin which may be stretchy
• Abnormal wound healing and scar formation
• Low muscle tone and Muscle weakness
• Early onset of osteoarthritis
• Cardiac effects: Dysautonomia typically accompanied by 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) ^[4]

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, Occipitoatlantoaxial hypermobility ^[5], Arnold-Chiari malformation ^[6]
• Functional bowel disorders (functional gastritis, irritable bowel syndrome)
• Nerve compression disorders (carpal tunnel syndrome, acroparesthesia, neuropathy) ^[7]
• Vascular skin conditions: Raynaud's phenomenon, Livedo reticularis
• Fibromyalgia symptoms: Myalgia and arthralgia ^[8]
• otosclerosis (hearing loss) ^[9]
• Premature rupture of membranes during pregnancy
• Platelet aggregation failure (platelets do not clump together properly) ^[10]
• 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
• Arterial/intestinal/uterine fragility or rupture

Because it is often goes undiagnosed in childhood, some instances of Ehlers-Danlos syndrome have been mischaracterized as child abuse.^[11] The pain associated with this condition is a serious complication.

Classification

In the past, there were more than 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.^[12] 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, 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 presentation of symptoms which may confuse classification of individuals on purely symptomatic basis. In order of prevalence in the population, they 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. Extreme flexibility is the hallmark of this type.	130020	COL3A1, TNXB
Classical	types 1 & 2	Affects approximately 2 to 5 in 100,000 people. It is caused by autosomal dominant mechanism and affects type-V collagen, as well as type I. Type 1 typically presents with severe skin involvement, and type 2 presents with mild to moderate skin involvement.	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 more prone to tearing (rupture). Patients with EDS type 4 often express a characteristic facial appearance (large eyes, small chin, 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) 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 dominant 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), fragile eyes, and severe muscle weakness.	225400, 229200	PLOD1
Arthrochalasis	types 7A & B	Is also very rare, with about 30 cases reported. It affects type-I collagen. The arthrochalasia type is characterised by very loose joints and dislocations involving both hips.	130060	COL1A1, COL1A2
Dermatosparaxis	type 7C	Also very rare, with about 10 cases reported. The dermatosparaxis type is characterised by extremely fragile and sagging skin.	225410	ADAMTS2

Other types

Although the above 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. So patients should not rely on the "fact" of having a certain type of EDS if cross-over symptoms are evident and might 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." [8] 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 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

Genetics

Mutations in the following can cause Ehlers-Danlos syndrome:

• Fibrous proteins: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, and TNXB
• Enzymes: ADAMTS2, PLOD1

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 throughout the body. 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. Please 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 clinical observation. Both DNA and biochemical studies can be 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 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.

Epidemiology

Ehlers-Danlos Syndrome is an inherited disorder estimated to occur in about 1 in 5000 births worldwide. Ehlers Danlos affects both males and females of all racial and ethnic backgrounds. Initially, prevalence estimates have previously 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. The prevalence of the six types differs dramatically. The most commonly occurring type is the hypermobility type, followed by the classical type. The other types of EDS are very rare. For example, fewer than 10 infants and children with the dermatosparaxis type have been described worldwide.

Treatment/management

There is no known cure for Ehlers Danlos Syndrome. The treatment is supportive. Close monitoring of the cardiovascular system, 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.

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,^[13] 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. ^[14]

EDS-like symptoms in animals

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.

Pop culture

The condition was brought to the mainstream on the series CSI New York in the first season episode Blood, Sweat and Tears. It was again featured in the FOX series Bones in the season 4, episode "The Perfect Pieces in the Purple Pond". EDS was also briefly mentioned on House M.D. in the episode titled "House's Head".

The condition is mentioned in the song Dorsal Horn Concerto by the British comedy band the Amateur Transplants. ^[15]

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.^[16]

The condition is at the center of 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. The episode parallels the murder of Doctor George Tiller of Wichita, Kansas.

See also

• Abdominal aortic aneurism
• Arnold-Chiari malformation
• Dislocations
• Dural ectasia
• Dysautonomia
• Gorlin sign
• Hypermobility
• Marfan syndrome
• mitral valve prolapse
• Postural orthostatic tachycardia syndrome
• Subluxations
• Tethered spinal cord syndrome
• Tricuspid regurgitation
• Wrinkly skin syndrome

References

1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Page 512. ISBN 0721629210.
2. ^ "Uncovered: How U.S. Health System Can Fail Even the Insured --- A Woman Endures 16-Month Odyssey To Get a Diagnosis", John Carreyrou, Wall Street Journal, November 16, 2007
3. ^ Lawrence EJ (2005). "The clinical presentation of Ehlers-Danlos syndrome". Adv Neonatal Care 5 (6): 301–14. doi:10.1016/j.adnc.2005.09.006. PMID 16338669. 
4. ^ [[1]]
5. ^ [2]
6. ^ [3]
7. ^ [4]
8. ^ [5]
9. ^ Medical Hear-It
10. ^ [6]
11. ^ The Press Enterprise, Redlands mother stung by untrue suspicions presses for accountability in child abuse inquiries, 2008-04-03
12. ^ Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1998). "Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK)". Am J Med Genet 77 (1): 31–7. doi:10.1002/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O. PMID 9557891. 
13. ^ PubMed
14. ^ [7]
15. ^ http://www.youtube.com/watch?v=OGXn6HuCodE&feature=PlayList&p=838DA384930CD363&index=13
16. ^ Yücel, D (January 1995). "Was Paganini born with Ehlers-Danlos syndrome phenotype 4 or 3?". Clin Chem 41 (1): 124-5. PMID 7813066. 

External links

Information

• University of Washington Medicine Multi-page explanation of EDS, including symptoms, genetics, diagnosis, and treatment
• National Institute of Health on Hypermobility EDS
• eds at NIH/UW GeneTests
• Joint & Bone - Ehlers-Danlos/Joint Hypermobility Syndrome - Proprioception

Organizations

• Ehlers-Danlos National Foundation (USA)
• EDS Network C.A.R.E.S. Foundation (USA)
• Ehlers-Danlos Support Group (UK)
• Ehlers Danlos Foundation of New Zealand

v • d • e Genetic disorder: Scleroprotein disease Extracellular matrix Collagen disease Genetic COL1: Osteogenesis imperfecta · Ehlers-Danlos syndrome, types 1,2,&7 COL2: Hypochondrogenesis · Achondrogenesis type 2 · Stickler syndrome · Marshall syndrome · Spondyloepiphyseal dysplasia congenita (see also C2/11) COL3: Ehlers-Danlos syndrome, types 3&4 (Sack-Barabas syndrome) COL4: Alport syndrome COL5: Ehlers-Danlos syndrome, types 1&2 COL6: Bethlem myopathy · Ullrich congenital muscular dystrophy COL7: Epidermolysis bullosa dystrophica COL8: Fuchs' dystrophy COL9: Multiple epiphyseal dysplasia COL10: Schmid metaphyseal chondrodysplasia COL11: Weissenbacher-Zweymüller syndrome · Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: Bullous pemphigoid Autoimmune Goodpasture's syndrome Laminopathy Barraquer-Simons syndrome · Buschke-Ollendorff syndrome/Osteopoikilosis · Pelger-Huet anomaly · Junctional epidermolysis bullosa Keratinopathy/ (keratosis, keratoderma, hyperkeratosis) Steatocystoma multiplex · Epidermolytic hyperkeratosis · Epidermolysis bullosa simplex · Ichthyosis bullosa of Siemens · Meesmann juvenile epithelial corneal dystrophy see also proteins

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)