Diagnosing Ehlers-Danlos Syndrome

Symptoms and Diagnosis

Ehlers-Danlos Syndrome affects all races and ethnic groups. The diagnosis of EDS is made upon clinical grounds first, skin hyperelasticity, easy bruising, dystrophic scarring, and joint hypermobility are the cardinal symptoms, which may be present in different combinations and with variable severity.  A full medical and family history should be taken.  Diagnosis is often impossible to make in infants and small children as abnormal joint hypermobility and skin elasticity are difficult to recognize, however, babies may present as floppy infants.  In children, joint hypermobility and hypotonia may cause delayed motor development, problems with walking e.g. frequent stumbling, and mild motor disturbances often thought to be clumsiness.  Other characteristics can be mitral valve prolapse, hernia, rectal prolapse, gastrointestinal diverticula, blue sclerae and easy inversion of the upper eyelid.

For Classic, Vascular, Dermatosparaxis and Kyphoscoliosis EDS types there are laboratory tests which may confirm or exclude the diagnosis.  For EDS types Hypermobility and Arthrochalasia there is no biochemical marker and a diagnosis is made on the basis of symptoms and family history.  Electron microscopic examination of a skin biopsy may reveal changes in the structure of collagen fibers, which is not specific but can be used as a diagnostic criterion for EDS in the absence of a biochemical marker.  In some patients an unequivocal classification cannot be made.  Coagulation tests are normal.

Classic and Hypermobility Types

These two types of Ehlers-Danlos Syndrome comprise 90% of all cases.

JOINTS

Hypermobility

Joint hypermobility is assessed by means of a method adapted from one first described by Carter and Wilkinson (1967).  The patient scores one point for the ability to perform each of the following tests, therefore giving a score of up to nine.  For comparison, most healthy subjects score 0-1, a  score of 5 is needed for a diagnosis of hypermobility.

  1. Passive dorsiflexion of each little finger beyond 90 degrees with the forearm flat on a table.
  2. Passive opposition of each thumb to the flexor aspect of the forearm.
  3. Hyperextension of each knee beyond 10 degrees.
  4. Hyperextension of the elbow beyond 10 degrees.
  5. Forward flexion of the trunk so that the palms of the hands rest easily on the floor.

SKIN

Texture and Characteristics

The skin has a soft velvety consistency, similar to wet chamois leather, it extends easily and snaps back after release.  Some other skin signs are: mild epicanthic folds; elevated cutaneous nodules at the knees and elbows and subcutaneous fatty cysts.  Lacerations of the skin may follow even mild trauma.  Wound healing is poor and ‘cigarette paper’ scars are common.  Skin can be discolored over the elbows, knees and shins and hematoma may be present.

Hyperextensibility

The degree of skin extensibility varies from patient to patient, and between various sites of the body, the skin of the ventral aspect of the forearm is lifted at a point midway between the elbow and the wrist joint.  The distance to which this skin fold can be stretched without causing discomfort is measured in centimeters.  An extensibility score (from 0-5) is calculated on the following basis:

Less than 4 cm, 0.5 cm, 2.7 cm = 4

More than 4 cm, 1.6 cm, 3.8 cm = 5

Scarring

A score of one was given for each of 5 bony points that bore more than 2 scars which were over 2 centimeters in length.  The areas which were assessed are both elbows, both knees, and the forehead.

Bruising

The severity of the bruising tendency is scored 0-5 on the following basis:

0     no history or clinical history of bruising.

1     a history of mild bruising, but no clinical evidence.

2     A history of moderate bruising, or of bleeding, with or without positive clinical findings.

3     Moderate bruising found on clinical examination.

4    Marked bruising found on clinical examination

This facet of the condition is not easy to assess.

ALL TYPES

There are approximately 6 different types of EDS which have been distinguished.  Differences within types may reflect inter/intra familial variability or genetic heterogeneity.  The present classifications based on a combination of clinical, genetic, and biochemical criteria will be revised, as molecular defects become clearer.

Victoria Hall / January 21, 2015 / EHLERS-DANLOS SYNDROME / 0 Comments

Types of Ehlers-Danlos Syndrome

Ehlers- Danlos Syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders characterized by articular hypermobility, skin extensibility and tissue fragility. There are six major types of EDS.  The different types of EDS are classified according distinct features.

Classical Type

Marked skin hyperextensibility with widened atrophic scars and joint hypermobility are found.  The skin manifestations range in severity from mild to severe expression.  The skin is smooth and velvety with the evidence of tissue fragility including; hiatal hernia, anal prolapse in childhood and cervical insufficiency.  Hernias may be a post-operative complication.  Also evident are molluscoid pseudotumors frequently found over pressure points and subcutaneous spheroids which are mobile and palpable on the forearms and shins.

Complications of joint hypermobility include sprains, dislocations/subluxations and pes planus.  Recurrent  subluxations are common in the shoulder, patella and temporomandibular joints.  Muscle hypotonia, delayed gross motor development may be evident.

Abnormal electrophoretic mobility of the proa 1(V) or proa 2(V) chains of collagen type V has been detected. Autosomal dominant inheritance.

Hypermobile Type

The skin involvement (hyperextensible and/or smooth, velvety skin) as well as bruising tendencies are both variable.  Joint hypermobility is the dominant clinical manifestation.  Generalized joint hypermobility that affects large and small joints is evident in Hypermobile Type EDS.  Recurring joint dislocations are common occurrences.  Certain joints, such as the shoulder, patella, and temporomandibular joint dislocate frequently.

Chronic joint and limb pain is a common complaint amongst individuals with Hypermobile Type EDS.  Skeletal X-rays are normal.  Musculoskeletal pain is early onset, chronic and may be debilitating.  The anatomical distribution is wide, tender points are often elicited.

To date, researchers have identified no distinctive biochemical collagen finding.  Autosomal dominant inheritance.

Vascular Type

Thin translucent skin reveals the subcutaneous venous pattern, and is particularly apparent over the chest and abdomen.  Facial appearance is characteristic in some affected individuals.  A decrease in subcutaneous tissue, particularly in the face and extremities is evident.  Minor trauma can lead to extensive bruising.  Arterial/intestinal/uterine fragility or rupture commonly arise in this type of EDS.  Spontaneous arterial rupture has a peak incidence in the third or fourth decade of life, but may occur earlier.  Midsize arteries are commonly involved.  Arterial rupture is the most common cause of sudden death. Life expectancy is shortened with a majority of individuals.

Joint hypermobility is usually limited to the digits.  Tendon and muscles rupture can occur.  Talipes equinovarus is frequently seen at birth.  Other manifestations that may be found in include: acrogeria; early onset varicose veins; arteriovenous, carotid-cavernous fistula; pneumothorax/pneumohemothorax; gingival recession and complications during and after surgery.

Vascular Type EDS is caused by structural defects in the proa` 1 (III) chain of collagen type III encodes by COL3A1. Autosomal dominant inheritance.

Kyphoscoliosis Type

Generalized joint laxity and severe muscle hypotonia at birth are seen in this type of EDS.  Muscular hypotonia can be very pronounced and leads to delayed gross motor development.  Individuals present with scoliosis at birth that is progressive.  The phenotype is most often severe, frequently resulting in the loss of ambulation in the second or third decade.  Scleral fragility may lead to rupture of the ocular globe after minor trauma.

Tissue fragility including atrophic scars and easy bruising may be seen.  Spontaneous arterial rupture can easily occur.  Other findings may include:  marfanoid habitus; microcornea; and radiologically considerable osteopenia.

Kyphoscoliosis Type EDS is the result of a deficient lysyl hydroxylase (PLOD). Autosomal recessive inheritance.

Arthrochalasia Type

Congenital hip dislocation is present in all and severe generalized joint hypermobility with recurrent subluxations; skin hyperextensibility with easy bruising, tissue fragility including atrophic scars; muscle hypotonia; kyphoscoliosis and radiologically mild osteopenia.

Arthrochalasia Type EDS is caused by mutations leading to deficient processing of the amino-terminal end of proa 1(I) [type A] or proa 2 (I) [type B] chains of collagen type I. Autosomal dominant inheritance.

Dermatosparaxis Type

Individuals demonstrate severe skin fragility bruising.  Wound healing is not impaired and the scars are not atrophic, skin texture is soft and doughy.  Sagging, redundant skin is evident.  The redundancy of facial skin results in an appearance resembling cutis laxa.  Large hernias (umbilical, inguinal) may also be seen.

Dermatosparaxis Type EDS is caused by a deficiency of procollagen I N-terminal peptidase.  Autosomal recessive inheritance.

Prognosis

The prognosis of EDS depends on the specific type. Life expectancy can be shortened with the Vascular Type of EDS due to the possibility of organ and vessel rupture. Life expectancy in all other types is normal.

Reference:

Beighton, P., De Paepe, A., Steinmann, B., Tsipouras, P., & Wenstrup, R. (in press). Ehlers-Danlos Syndrome: Revised Nosology, Villefranche, 1997. American Journal of Medical Genetics.

Amy William / January 19, 2015 / EHLERS-DANLOS SYNDROME / 0 Comments

EHLERS-DANLOS SYNDROME – The Role of Collagen in the Eye

ABSTRACT

Ehlers Danlos syndrome (EDS) is a group of heritable connective tissue disorders characterized by hyperextensible skin, hypermobile joints, and connective tissue fragility.1  These symptoms are believed to be the result of gene mutations affecting the structure or assembly of different collagen types.  The eye is made up of 80% collagen.  Therefore, it is recommended that individuals with EDS be seen at least annually by an optometrist or ophthalmologist for a full evaluation of their eye health.  This article attempts to explain common ophthalmologic findings and their symptoms.  The symptoms discussed in this article occur in the normal population and are not exclusive to EDS.  However, due to the involvement of collagen and its role in the eye, individuals with EDS may have a higher incidence of ophthalmic implications, especially in the Kyphoscoliosis Type of EDS (formerly known as Type VI).1  Additional research in this area is needed.  This article is based on two presentations by Dr. Stephanie Kirschbaum to the Northern California Branch of the Ehlers Danlos National Foundation.

ROLE OF COLLAGEN IN THE EYE

The human eye is primarily made up of connective tissue.  The sclera (the tissue that makes up the white of the eye) is all collagen and represents 80% of the eye.  The cornea (clear tissue at the front of the eye) is mostly collagen as well.4  Since EDS is a collagen defect and the eye is primarily made of collagen, individuals with EDS in particular may experience ocular changes.1, 4  An optometrist or ophthalmologist should be consulted for a comprehensive eye exam to establish the patient’s baseline medical data.  This first exam should include a complete history and examination of all parts of the eye.  Dilation of the pupil will allow for thorough examination of the internal parts of the eye.  With annual follow-up exams, an eye physician should be able to identify any ocular changes.  The presence and nature of any pain, discharge, redness or changes in visual acuity require further evaluation.  Any disturbance in vision demands an explanation.  If retinal changes occur, follow up frequency should be at least every six-months.  For floaters (floating spots behind the lens of the eye, usually harmless and not visible during normal visual activities) suggested follow-up frequency is every three months.  Patients experiencing flashes of light should report this immediately to their primary eye care physician.

Many factors may effect ocular changes; genetics, nutrition, computer usage, environment and overwork.  The strength and sensitivity of the collagen in the eye appear to be responsive to overuse.  Overuse or overworking of the eyes can be defined as excessive reading, television viewing, or computer screen use without blinking or looking away every few seconds and taking a break from the activity after one hour.  While reading, that would translate into looking away after every page and putting the material down after an hour to focus on another activity for a few minutes.

Many articles identify ophthalmologic findings of individuals or small groups of patients with an Ehlers-Danlos syndrome diagnosis.1, 2, 3, 4, 5, 6  Findings identified in these articles are:

Epicanthal Folds Keratoconus
High Myopia Blue Sclera
Lens Subluxation Retinal Detachments
Angioid Streaks Strabismus
Carotid-cavernous sinus fistulas Photophobia
Posterior Staphyloma Glaucoma
Cataracts Macular Degeneration
Dry Eyes

Note that these findings also occur in the normal population and that no research to date compares their occurrence within the general population to that of individuals with EDS.  Major diagnostic criteria for the Kyphoscoliosis Type of EDS include scleral fragility and ocular rupture.1

EPICANTHAL FOLDS

An epicanthal fold is an extra fold of skin covering the inner corner of the eye.  They are caused by the hyperextensibility of or an excess of eyelid skin.  The excess skin causes a fold in the area closest to the nose.  Epicanthal folds are commonly found in the Classical Type of EDS4 and people of Asian ancestry.

KERATOCONUS

The cornea is the clear membrane at the front of the eyeball.  Keratoconus is a type of abnormal corneal curvature that occurs when the cornea becomes cone-shaped.2, 4  It usually happens during the second or third decade of life and will cause images to be distorted.  It is believed to be more common amongst people with lots of allergies (atopic).  Gas permeable contact lenses are helpful.  As a last resort, corneal transplant is required.  Keratoconus can lead to blindness.2, 3

HIGH MYOPIA 

High Myopia is characterized by nearsightedness where items in the distance become blurry.  The nearsightedness results because the eye is too long or the cornea is too steep so the focus point of light rays entering the pupil is in front of the retina.  Corrective lenses are an effective treatment for high myopia.2, 3

BLUE SCLERA 

The sclera is the white of the eye or the thick outer coat of the eyeball. =20A bluish appearance is attributed to a thinning of the sclera.  The thinning is most noticeable at the limbus (where the cornea meets the white of the eye) thus creating the a blue “halo” at the limbus.  The blue halo becomes less prominent with aging and the normal decrease in scleral transparency.  Blue sclera is considered to be a prominent feature of osteogenesis imperfecta and EDS.3, 4, 6

LENS SUBLUXATION

The lens, located behind the pupil, bends light rays as they enter the eye so that they focus on the retina in the back of the eyeball.  The signals travel to the brain where they are translated into images.  The lens is suspended by ligaments and may sublux, or come loose, sometimes falling into the posterior of the eye, causing an inability for light to focus in the eye.  The lens is made up of epithelial cells that grow in many layers, like an onion.  It grows throughout a person’s lifetime.  With normal aging, thickness and loss of resiliency can cause focusing to be more sluggish.  This is known as presbyopia, or the need for magnifying glasses after age 40.2, 3, 4

RETINAL DETACHMENTS

The retina is the innermost layer of the eye upon which light rays are focused.  As the eye lengthens or expands, the retina is more loosely attached than in infancy.  A piece of the retina may detach itself and be trapped within the vitreous or the inside gel of the eye.  A retinal detachment may be preceded by a shower of sparks, floaters,  or lightening flashes then a ‘curtain’ falls across the visual field.  THIS IS AN EMERGENCY.  Floaters are trapped debris, usually a clumping of protein, in the vitreous gel of the eye.  Most people have floaters which prove to be harmless, but they should always be reported to the eye care professional to be certain.3, 4, 6

ANGIOID STREAKS

Angioid streaks are cracks in the Bruch’s membrane, the basement or “anchoring” membrane of the retina.  The “streaks” usually radiate from the optic disc and appear as changes in the color of the retina.  Through aging, the Bruch’s membrane thickens, but if there is a defect in any of the collagen layers of the membrane, streaks appear.  It is as if one dipped an uninflated balloon in paint and let it dry.  As the balloon is inflated, cracks appear in the paint.  Angioid streaks are common to many systemic disorders including Sickle cell, epilepsy, Marfan syndrome, Paget’s disease, and EDS.3, 4, 6

STRABISMUS

A strabismus occurs when the resting eye is in a position other than at the center.  A group of six muscles hold the eye in place and enable it to move around.  Both eyes normally move in concert with one another.  If any one of the muscles is weaker than the others, the eye will drift or cross.  Loose tendons and ligaments around the eye create hard working muscles that get tired.  Over active muscles will not work efficiently.  Multifocal lenses (bifocals or trifocals) can help to balance the muscle activity associated with changing focus from faraway to close up and back to distance, as when driving.  Prism in prescription glasses can be helpful in directing light to the correct spot on the retina.  Avoid intentionally crossing the eye or moving one eye out of synch from the other.  Surgical repair of a strabismus may be further complicated because sutures are difficult to place in thinned sclera.  Surgical repair may not have lasting effects if the cause is a non-uniform elasticity of the tendons and ligaments associated with the eye muscles.3, 4

CAROTID-CAVERNOUS SINUS FISTULAS 

A carotid-cavernous sinus fistula is very much like an aneurysm.  It is the rupture of a blood vessel which bleeds into a sinus cavity and/or some part of the eye.  The blood flow can cause serious structural damage to the eye.=20 THIS IS AN EMERGENCY.  Individuals report hearing their pulse in their temple and having a frontal headache on one side or the other.  A doctor will look for it by placing a stethoscope over the temple and listening for a ‘whooshing’ sound.  Carotid-cavernous sinus fistulas commonly found in Vascular, formerly called Type IV EDS, but all types and the normal population are susceptible as well.3, 4, 5

PHOTOPHOBIA

Photophobia is an intolerance to light or glare.  Light-eyed people are more susceptible to this kind of glare.  It may re relieved by tinted, glare-resistant or dark UV protected glasses.  Sudden photophobia should be reported to an eye care professional immediately.

POSTERIOR STAPHYLOMA

Posterior staphyloma is a stretching or distortion in the back of the eye.  Scleral tissue “bubbles” which results in a significant myopic shift (increased nearsightedness.)4

GLAUCOMA

Glaucoma is an increase or change in the intraocular pressure which leads to vision impairment ranging from slight changes to blindness, as well as a progressive loss of peripheral vision.  Glaucoma is irreversible if it is identified too late in the progression of the symptoms.  It is believed to be caused by nearsightedness, heredity, injury, diabetes, vascular and mechanical irregularities.2, 3, 4

CATARACTS

A cataract is a cloudy lens.  The lens tissue discolors naturally as a result of sclerosis, or hardening, as one matures.  It becomes more golden in color as it thickens which also decreases vision.  Premature cataracts can occur from UV exposure, diabetes or nutritional factors.3, 4

MACULAR DEGENERATION

Macular degeneration occurs when the macula atrophies causing pigment changes and a decrease in keen vision to occur.  The macula, the strongest part of the retina, contains the highest concentration of vision receptors.  There are two kinds of macular degeneration: wet and dry.  In wet macular degeneration the underlying retinal blood vessels break or leak.  Dry macular degeneration is a deterioration or “wearing out” of the retina.  High risk factors include chronic UV exposure, smoking, inadequate nutrition, and heredity.3, 4

DRY EYES

Dry eyes result when the normal coating of tears on the eye is diminished.  This can result if one doesn’t blink regularly or under dry environmental conditions.  Dry eyes should not be treated with bottled eye drops that have a preservative in them.  Instead, drink plenty of water, blink frequently, use a warm compress on eyes and/or use eye drops that do not have a preservative.  Preservative free eye drops come in packages of single use containers.3

KYPHOSCOLIOSIS TYPE EDS

Kyphoscoliosis Type EDS is caused by a reduction in the normal activity of the enzyme lysyl hydroxylase which is required for the assembly of collagen fibrils.  This type of EDS may include the progressive loss of pigment tissue in the eye.  Improper drainage of the fluid of the eye may lead to increased intraocular pressure which promotes the incidence of glaucoma.  Scleral fragility and ocular rupture are possible with this type of EDS.1, 3, 4

SUMMARY

Since the eye is primarily collagen, anyone with a preexisting collagen disorder or defect must pay particular attention to any and all ocular changes.  A yearly eye exam is as important as a yearly physical.  The presence and nature of any pain, discharge, redness or any changes in visual acuity require an immediate evaluation.  Begin with a thorough medical eye exam performed by an optometrist or ophthalmologist to establish a baseline eye health profile.  If changes in vision or eye health occur, consult your eyecare professional as soon as possible.

Amy William / January 18, 2015 / EHLERS-DANLOS SYNDROME / 0 Comments

WHAT IS EHLERS-DANLOS SYNDROME?

Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a tough, fibrous protein, plays an essential role in “holding together,” strengthening, and providing elasticity to bodily cells and tissues. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, “stretchy” (elastic) skin; and excessive fragility of the skin, blood vessels, and other bodily tissues and membranes.

The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form’s associated symptoms and findings (clinical evidence) and underlying cause. A revised, simplified classification system (revised nosology) has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance.

Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). In other words, parents with one subtype of EDS will not have children with another EDS subtype. Depending upon the specific subtype present, Ehlers-Danlos syndrome is usually transmitted as an autosomal dominant or autosomal recessive trait.

Symptoms

The symptoms and findings associated with Ehlers-Danlos syndrome (EDS) may vary greatly in range and severity from case to case, depending upon the specific form of the disorder present and other factors. However, the primary findings associated with EDS typically include abnormal “looseness” (laxity) and excessive extension (hyperextension) of joints; susceptibility to partial or complete joint dislocations; chronic joint pain; a tendency to develop degenerative joint disease (osteoarthritis) at an early age; unusually loose, thin, elastic skin; and excessive fragility of the skin, blood vessels, and other bodily tissues and membranes. Due to tissue fragility, affected individuals may easily bruise; experience prolonged bleeding (hemorrhaging) after trauma; have poor wound healing; develop “parchment-like,” thin scarring; and/or have other associated abnormalities.

In many individuals with EDS, associated symptoms and findings may become apparent during childhood. More rarely, depending upon the specific disorder subtype present, certain abnormalities may be apparent beginning at birth (congenital). In addition, in other individuals, such as those with mild disease manifestations, the disorder may not be recognized until adulthood.

The different forms of EDS were formally classified in the 1980s using a Roman numeral system. This categorization identified at least 10 major forms of the disorder based upon genetic and biochemical abnormalities as well as associated symptoms and findings. However, a simplified, revised, updated classification system has since been published in the medical literature that classifies EDS into six primary subtypes as well as some other forms of EDS, based upon the specific underlying biochemical cause, mode of inheritance, major and minor symptoms, and physical findings. The revised classification system serves to further differentiate between the various forms of the disorder as well as some related disorders.

The original classification system differentiates between severe and mild forms of classic EDS (EDS I and II). In the revised categorization, EDS I and II are reclassified as one subtype, known as EDS classical type. According to reports in the medical literature, in individuals with this subtype, associated skin abnormalities may vary greatly, ranging from mild, moderate, to severe in certain affected families (kindreds). EDS classical type may be characterized by excessive laxity and extension of the joints (hypermobility); susceptibility to recurrent sprains and dislocations of certain joints, such as the knees and shoulders; abnormally increased elasticity and extension (hyperextensibility) of the skin; and tissue fragility, potentially leading to degeneration or “splitting” of the skin, abnormal healing of skin wounds, and characteristic, thin, “parchment-” or “paper-like” (papyraceous) scarring that often becomes discolored and widened. Such scarring may occur primarily over certain prominent bony areas (pressure points), such as the shins, knees, elbows, and forehead. In individuals with EDS classical type, additional findings may include the formation of relatively small, fleshy, tumor-like skin growths (molluscoid pseudotumors) and/or hard, round, movable lumps (calcified spheroids) under the skin; unusually “velvety” skin; diminished muscle tone (hypotonia); and/or flat feet (pes planus). EDS classical type may also be characterized by easy bruisability, often occurring in the same areas; abnormal displacement (prolapse) of certain organs due to tissue fragility, such as protrusion of part of the stomach upward through an opening in the diaphragm (hiatal hernia); and/or an increased risk of certain complications after surgical procedures. For example, postsurgical complications may include protrusion of certain organs through weak areas in surrounding membranes, muscles, or other tissues (postsurgical hernias). In addition, some individuals with this subtype may have a deformity of one of the heart valves (mitral valve prolapse), allowing blood to leak backwards into the left upper chamber of the heart (mitral insufficiency), and/or, more rarely, abnormal widening (dilatation) of a region of the aorta, the major blood vessel of the body.

EDS hypermobility type was formerly classified as EDS III or benign hypermobility syndrome. This form of the disorder is primarily characterized by generalized, excessive extension (hypermobility) of the large and small joints. Additional findings may include abnormally increased skin elasticity, an unusually smooth or “velvet-like” consistency of the skin, and/or easy bruising. Skin abnormalities and bruising susceptibility may be extremely variable from case to case. Some individuals with EDS hypermobility type may develop chronic, potentially disabling joint pain and be prone to recurrent dislocations, particularly of the knee, shoulder, and jaw (i.e., temporomandibular) joints.

EDS vascular type (formerly EDS IV or EDS arterial-ecchymotic type) is primarily characterized by unusually thin, transparent skin with prominent underlying veins, particularly in the chest and abdominal areas; a susceptibility to severe bruising from minor trauma; and tissue fragility, potentially resulting in spontaneous rupture of certain membranes and tissues. For example, affected individuals may be prone to spontaneous rupture of certain mid-sized or large arteries or the intestine (bowel), leading to life-threatening complications. Because acute pain in the abdominal or flank area may indicate possible arterial or intestinal rupture, such symptoms require immediate, emergency medical attention. Individuals with EDS vascular type may also be prone to developing abnormal channels between certain arteries and veins (arteriovenous fistula, e.g., carotid-cavernous sinus fistula) and have an increased risk of weakening of arterial walls and associated bulging of certain arteries (aneurysms), such as those supplying the head and neck (carotid arteries) and within the skull (intracranial). Aneurysms may be prone to rupturing, potentially resulting in life-threatening complications. Females with EDS vascular type may also be at risk for arterial bleeding and rupture of the uterus during pregnancy as well as vaginal tearing, uterine rupture, and/or other complications during delivery. In addition, affected individuals may be prone to experiencing certain complications during and after surgical procedures, such as separation of the layers of a surgical wound (dehiscence).

Individuals with EDS vascular type may also have abnormally decreased levels of fatty tissue under skin layers (subcutaneous adipose tissue) of the hands, arms, legs, feet, and face. As a result, some affected individuals may have a characteristic facial appearance, including thin lips; a thin, pinched nose; relatively large, prominent eyes; hollow cheeks; and tight, lobeless ears. In addition, skin of the hands and feet may appear prematurely aged (acrogeria). Additional symptoms and findings associated with this EDS subtype may include a deformity in which the foot is twisted out of position at birth (clubfoot); hypermobility that may be limited to joints of the fingers and toes (digits); the early onset of varicose veins, which are unusually widened, twisted veins visible under the skin; and spontaneous rupture of muscles and tendons. In addition, some with this EDS subtype may be susceptible to abnormal accumulations of air and blood in the chest cavity (pneumohemothorax) and/or associated collapse of the lungs (pneumothorax).

In individuals with EDS kyphoscoliosis type (formerly EDS VI), certain symptoms and findings may be apparent at birth (congenital). These include abnormal sideways curvature of the spine (congenital scoliosis) that becomes progressively severe; diminished muscle tone (hypotonia); and generalized, excessive extension and looseness (laxity) of the joints. In children with the disorder, severe hypotonia may cause delays in the acquisition of certain motor skills, and affected adults may lose the ability to walk by the second or third decade of life. Additional findings associated with EDS kyphoscoliosis type may include easy bruising, tissue fragility and associated degenerative (atrophic) scarring of the skin, a risk of spontaneous arterial rupture, abnormally reduced bone mass (osteopenia), and unusually small corneas (microcornea). In addition, because the opaque, inelastic membrane covering the eyeballs (sclera) may be unusually fragile, minor trauma may result in rupture of the sclera, rupture of the transparent region in the front of the eyes (cornea), and/or detachment of the nerve-rich membrane in the back of the eyes (retina).

EDS arthrochalasia type (formerly EDS VII, Autosomal Dominant [EDS VIIA and VIIB]) is primarily characterized by dislocation of the hips at birth (congenital hip dislocation); severe, generalized, excessive extension of the joints (hypermobility); and recurrent partial dislocations of affected joints (subluxations), such as those of the elbows, knees, hips, and feet. Affected individuals may also have diminished muscle tone (hypotonia), abnormal front-to-back and sideways curvature of the spine (kyphoscoliosis), and mildly reduced bone mass (osteopenia). Additional findings typically include abnormally increased elasticity and extension of the skin (hyperextensibility), easy bruising, and tissue fragility, with associated scarring of the skin.

Primary symptoms and findings associated with EDS dermatosparaxis type (formerly EDS VII, Autosomal Recessive [EDS VIIC]) include severe skin fragility; soft, sagging, redundant skin; and extensive bruising. In some cases, certain tissues or organs may abnormally protrude through a weak area in a surrounding membrane, muscle, or other tissue (e.g., umbilical hernia, inguinal hernia).

In addition to the six primary EDS subtypes described above, there are some additional, rare forms of EDS. For example, X-linked EDS (formerly EDS Type V) has been described in individuals within at least one family (kindred). Associated symptoms and findings include easy bruising, hyperextensible skin, minor skin fragility, and deformity of one of the heart valves (mitral valve prolapse), allowing blood to leak backwards into the left upper chamber of the heart (mitral insufficiency). Because this form of EDS is transmitted as an X-linked recessive trait, it is fully expressed in males only. (For more information on X-linked inheritance, please see the “Causes” section of this report below.)

The symptoms and findings associated with EDS periodontosis type (formerly EDS Type VIII) are considered similar to those seen in EDS classical type. Additional findings typically include disease of the tissues surrounding and supporting the teeth (periodontal disease), potentially resulting in premature tooth loss.

EDS progeroid form, another rare variant of the disorder, is characterized by loose, elastic skin; hypermobile joints; slow wound healing; degenerative (atrophic) skin scars; and reduced bone mass (osteopenia). Additional findings may include delayed mental development, short stature, and a prematurely aged appearance (progeroid appearance) due to premature wrinkling of facial skin; scanty scalp hair, eyebrows, and eyelashes; and other findings.

According to reports in the literature, some individuals may be affected by additional, rare subtypes of EDS, which are currently referred to as EDS unspecified forms. Such subtypes are characterized by joint hypermobility, loose, elastic skin, and other symptoms and findings commonly seen in individuals with the disorder.

The EDS subtype originally referred to as EDS type X (or EDS dysfibronectinemic type) is extremely rare, affecting only one reported family (kindred). This subtype is characterized by abnormally extensible, loose joints; thin, elastic skin; and abnormalities of the specialized blood cells that play an essential role in blood clotting (platelets). Associated findings typically include the appearance of tiny purplish or reddish spots on the skin due to abnormal bleeding within or under skin layers (petechiae) and/or pinkish, depressed scar-like skin lesions that may later become white (striae distensae). These lesions, which may occur on the thighs, abdomen, buttocks, and breasts, develop due to weakening of elastic tissues.

Some subtypes of EDS included within the original disease classification have been redefined and are no longer part of the original nor the revised EDS categorization. For example, what was previously known as EDS type IX has been redefined and is now termed occipital horn syndrome. In addition, EDS type XI is currently known as familial hypermobility syndrome. For more information on these disorders, please see the “Related Disorders” section of this report below.

Causes

Most forms of Ehlers-Danlos syndrome (EDS) are transmitted as an autosomal dominant or autosomal recessive trait. Each EDS subtype is a distinct hereditary disorder that may affect individuals within certain families (kindreds). In other words, individuals with one subtype of EDS will not have children with another EDS subtype.

The disease genes that cause some forms of EDS have been mapped to particular chromosomes. Although the specific underlying cause of EDS is not known for all EDS subtypes, the disorder is known to result from various defects of collagen, the major structural protein in the body. Collagen is the tough, fibrous protein that serves to provide elasticity to and strengthen bodily cells and tissues.

EDS classical type is inherited as an autosomal dominant trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

According to researchers, in at least some affected individuals, EDS classical type may result from abnormal changes (mutations) in the gene known as collagen type V, alpha-1 (COL5A1), which has been mapped to the long arm (q) of chromosome 9 (9q34.2-q34.3), or the gene collagen type V, alpha-2 (COL5A2), located on the long arm of chromosome 2 (2q31). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.

EDS hypermobility type is transmitted as an autosomal dominant trait. A specific underlying collagen defect responsible for this form of the disorder has not been identified. EDS vascular type is also inherited as an autosomal dominant trait. This subtype is caused by abnormal changes (mutations) of the gene known as collagen type III, alpha-1 (COL3A1), which is located on the long arm of chromosome 2 (2q31).

EDS kyphoscoliosis type is inherited as an autosomal recessive trait. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

In some affected individuals, the kyphoscoliosis subtype is thought to result from mutations of a gene (called “procollagen-lysine, 2-oxoglutarate 5-dioxygenase” [PLOD]) that encodes a collagen-modifying enzyme known as lysyl hydroxylase. Deficiency of this enzyme may result in the symptoms and findings associated with this form of EDS. The PLOD gene has been mapped to the short arm of chromosome 1 (1p36.3-p36.2).

EDS arthrochalasia type is transmitted as an autosomal dominant trait. This subtype may result from mutations of the gene known as collagen type I, alpha-1 (COL1A1), which has been mapped to the long arm of chromosome 17 (17q21.31-q22.05), or the gene called collagen type I, alpha-2 (COL1A2), located on the long arm of chromosome 7 (7q22.1).

EDS dermatosparaxis type has autosomal recessive inheritance. This EDS subtype is thought to be caused by mutations of a gene or genes that encode a collagen-modifying enzyme known as procollagen I N-terminal peptidase.

As discussed above (see “Symptoms”), in addition to the six primary EDS subtypes, there are some other, rare forms of EDS. The rare subtype known as X-linked EDS is, as its name indicates, transmitted as an X-linked trait. X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome may be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Males with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Females who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons. In some females who inherit a single copy of a disease gene for an X-linked recessive trait (heterozygotes), disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. Therefore, it is possible that some female carriers of the disease gene may exhibit some of the symptoms associated with the disorder; however, according to reports in the medical literature, to date, no female carriers of the disease gene for X-linked EDS have experienced symptoms (asymptomatic carriers).

EDS periodontosis type, another rare subtype, has autosomal dominant inheritance. EDS progeroid form, which is thought to be inherited as an autosomal dominant trait, may be caused by gene mutations that result in deficiency of a particular enzyme (XGPT deficiency). The subtype known as EDS type X (or EDS dysfibronectinemic type), which has been described in several siblings in one affected family (kindred), is thought to have autosomal recessive inheritance.

According to reports in the medical literature, there appear to be additional, rare subtypes of EDS that may have autosomal dominant or autosomal recessive inheritance (e.g., EDS, autosomal dominant, unspecified type; EDS, autosomal recessive, unspecified type).

Affected Populations

Males and females are equally affected by autosomal dominant and autosomal recessive forms of Ehlers-Danlos syndrome (EDS). The X-linked subtype of EDS is fully expressed in males only. It is possible that some females who carry a single copy of the disease gene (heterozygotes) for X-linked EDS may develop some symptoms; however, according to the medical literature, reports indicate that no female carriers have developed associated symptoms (asymptomatic).

In many individuals with EDS, associated symptoms and findings may become apparent during childhood. However, depending upon the form of the disorder present, some abnormalities may be apparent at birth. In other cases, such as those with relatively mild disease manifestations, EDS may not be recognized until adulthood.

Reported estimates concerning the disorder’s overall frequency have varied, ranging from one in 5,000 to 10,000 births. However, because those with mild joint and skin manifestations may not seek medical attention or remain undiagnosed, it is difficult to determine the true frequency of EDS in the general population. EDS classical, hypermobility, and vascular types account for most reported cases of the disorder. EDS kyphoscoliosis, arthrochalasia, dermatosparaxis, and other subtypes are considered much less common. For example, some forms of EDS (e.g., EDS type X or EDS dysfibronectinemic type) may have only been reported in individuals within one affected family (kindred).

The first published accounts of Ehlers-Danlos syndrome occurred in 1892. The syndrome was furthered clarified by Ehlers in 1901 and Danlos in 1908.

Related Disorders

Some of the symptoms of the following disorders may be similar to those seen in Ehlers-Danlos syndrome (EDS). Comparisons may be useful for a differential diagnosis:

Occipital horn syndrome (OHS), also known as X-linked cutis laxa, is a rare disorder that was formerly classified as a subtype of EDS (EDS type IX). The disorder has been recategorized with other connective tissue diseases that result from defects of copper metabolism. OHS is characterized by abnormally loose skin that tends to hang in folds (cutis laxa); abnormalities of the muscular organ that stores urine (bladder); the formation of “horn-like” bony protuberances on both sides of the back of the skull (occipital horns) and other skeletal abnormalities; excessive extension (hypermobility) of the fingers and toes; and limited extension of the elbows and knees. In some cases, affected individuals may have a prematurely aged facial appearance, a hooked nose, sagging cheeks, downwardly slanting eyelid folds (palpebral fissures), and/or other facial abnormalities. The disorder may also be characterized by mild mental retardation. OHS is transmitted as an X-linked recessive trait and is caused by deficiency of an enzyme (lysyl oxidase deficiency) that results in abnormalities of copper metabolism.

Familial hypermobility syndrome was also formerly categorized as a subtype of EDS (EDS type XI). However, researchers since suggested that the designation of EDS be reserved for the association of joint hypermobility with distinctive skin changes, resulting in the disorder’s separate categorization. Familial hypermobility syndrome is characterized by looseness (laxity) and excessive extension of the joints; recurrent dislocation of certain joints, such as those of the shoulders and knees; and, in some cases, dislocation of the hip joints at birth (congenital). This disorder is transmitted as an autosomal dominant trait.

There are additional disorders that may be characterized by joint hypermobility, skin changes, and/or other abnormalities similar to those associated with EDS, such as other forms of cutis laxa or other related disorders. (For more information on these disorders, please choose “cutis laxa” or other specific disease names as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis

Ehlers-Danlos syndrome (EDS) is diagnosed based upon a thorough clinical evaluation, characteristic physical findings, a careful patient and family history, and specialized tests.

Specialized diagnostic laboratory tests may be available for certain EDS subtypes in which the specific underlying biochemical defect has been identified and characterized. In addition, in some families (kindreds) affected by a particular EDS subtype who have identified gene mutations, precise genetic testing may be available that enables diagnosis before or after birth (prenatal or postnatal diagnosis). However, it is possible that such testing may only be accessible through research laboratories with a special interest in EDS.

In addition, in some cases, diagnostic testing includes the removal (biopsy) and microscopic examination (e.g., electron microscopy) of small samples of skin tissue. Such examination may reveal characteristic abnormalities in collagen structure seen in certain EDS subtypes.

The clinical evaluation of individuals with suspected or diagnosed EDS typically includes assessments to detect and determine the extent of skin and joint hyperextensibility. For example, physicians may measure skin hyperextensibility by carefully pulling up skin at a neutral site until the point of resistance, and joint hyperextensibility may be evaluated using a clinical rating scale (i.e., Beighton scale). In addition, in some cases, specialized imaging tests, such as computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and echocardiography, are used to detect and characterize mitral valve prolapse and aortic dilatation. During a CT scan, a computer and x-rays create a film showing cross-sectional images of certain bodily structures. MRI uses a magnetic field to create cross-sectional images of particular organs and tissues. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion.

In addition, in some individuals with EDS, specialized x-ray studies may be used to characterize round, movable lumps (calcified spheroids) under the skin; to detect and determine the extent of abnormal spinal curvature (scoliosis and/or kyphosis) and/or reduced bone mass (ostepenia) (e.g., in those with EDS kyphoscoliosis or arthrochalasia types); and/or to confirm and characterize certain other abnormalities.

In some cases, physicians may recommend that individuals with EDS vascular type be monitored with appropriate noninvasive imaging techniques (e.g., CT scanning, MRI, ultrasonography) to ensure early detection of arterial changes (e.g., aneurysms) that may result in spontaneous arterial rupture and potentially life-threatening complications. Angiography, a diagnostic test that is often used to detect aneurysms, must be avoided, since this technique may be hazardous to individuals with EDS, particularly those with EDS vascular type. During angiography, a substance that is impenetrable by x-rays (contrast medium) is injected into an artery via a flexible plastic tube (catheter) and an x-ray series is taken that visualizes blood flow through certain blood vessels.

Treatment

The treatment of individuals with EDS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected individual’s treatment. Such specialists may include pediatricians or internists; specialists who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who diagnose and treatment skin disorders (dermatologists); specialists who diagnose and treat connective tissue diseases (rheumatologists); surgeons; physical and occupational therapists; and other health care professionals.

In individuals with EDS, the use of special braces may help to stabilize affected joints. In addition, specialized physical and occupational therapy techniques may help to preserve the joints and strengthen muscles. Parents of young children with the disorder and affected individuals should also take necessary precautions to prevent injuries and trauma, such as may occur during contact sports. Wearing protective clothing and special padding over pressure points (e.g., shins, knees, elbows) may be beneficial.

Females with EDS vascular type should be counseled concerning the increased risk of certain complications during pregnancy and delivery and the need for meticulous obstetric care. In addition, appropriate precautions and careful monitoring are essential before, during, and after dental or surgical procedures. Because fragile tissues and stitched (i.e., sutured) incisions or wounds may easily tear during or after surgery, unnecessary surgical procedures should be avoided. Accordingly, when surgery is necessary in individuals with EDS, specific surgical approaches require careful evaluation.

Genetic counseling will be of benefit for affected individuals and family members. Other treatment for individuals with EDS is symptomatic and supportive.

Amy William / January 15, 2015 / EHLERS-DANLOS SYNDROME / 0 Comments

Patients Suffering from Ehlers-Danlos Syndrome type III Do Not Respond to Local Anesthetics

The classical features of Ehlers-Danlos Syndrome type III (EDS) are hyperextensibility of the joints, hyperelasticity and fragility of the skin. Only minor visible changes of the skin and joint hypermobility makes this syndrome difficult to distinguish from the more common simple hypermobility. Ehlers-Danlos syndrome is claimed to be a rare syndrome with an incidence of 1/150,000. Since we initiated our research on this syndrome, we have found 4 families in an area with about 300,000 inhabitants. The syndrome, therefore, seems to be more common than assumed and the reason why the syndrome is not diagnosed can be due to the fact that the syndrome is diagnosed as hypermobility.

 We have observed that local anesthesia has an insufficient effect in Ehlers-Danlos type III patients and that it is difficult to distinguish the Ehlers-Danlos type III syndrome from hypermobile patients diagnostically. In genetic advising and prognosis of the EDS patients, there is a need for new tools to separate them from hypermobile patients. We, therefore, investigated quantitatively if the Ehlers-Danlos type III patients objectively responded differently from hypermobile patients to cutaneous analgesia, and we sought to find out if these parameters could be used as a new test to discriminate between the two diseases.

Topical analgesics (EMLA cream) was applied to seven EDS patients, ten hypermobile patients, and to fifteen controls. The depth of the cutaneous analgesia was measured by sensory and pain threshold depths to controlled needle insertions. It should be easy to carry out the measurements in the daily clinical situation. EMLA cream is commonly available and insertion of the needle can be done without the special equipment used in this study. Controls and hypermobiles did not differ in their response to cutaneous analgesia. The thresholds to cutaneous laser simulation and the depth of analgesia increased significantly less in the Ehlers-Danlos patients, compared to the two other groups. In clinical practice, a needle insertion test can easily be applied to investigate if patients are responders or non-responders to local analgesics.

 When the Ehlers-Danlos type III patients were biopsied in the hip region for skin biopsy, they all reported considerable pain although large doses (5 ml) of 1% lidocaine-epinephrine were infiltrated subcutaneously. When we asked them for more details, they reported that they had all previously experienced difficulties in obtaining a sufficient analgesia at the dentist, although they had been given substantial doses of local analgesics. Some of the women reported no pain alleviation of local analgesics when they were sutured after episiotomy. They were commonly characterized as hysterics. We have definitely proved that this is not the case.

Victoria Hall / January 11, 2015 / EHLERS-DANLOS SYNDROME / 0 Comments