Calgary Corporate Tax Planning

corporatetaxaccountantHow can you reduce your tax liabilities? Is it even possible to pay less even though you are earning more? To some, this may sound too impossible, but with the right Calgary corporate tax planning, you can get away with less ta and more savings.

Corporate tax planning can be a very daunting task. Not everyone can do it. There are specialists who are really good about tax planning and they are the very people who are capable of minimizing your tax liabilities to almost nothing, you won’t even feel that there is tax to pay for to begin with.

The first step in corporate tax planning in Calgary is to look into the varying rules that every jurisdiction that your business covers has. The complexity of computing for tax discounts comes from the tangled rules that come from different areas and units. These fundamental issues need to be primarily resolved before real tax discounts are arrived at.

The corporate structure also seems to make it impossible to get away with less tax and earn more for some companies. The structure itself hinders the capacity of a company to get the discounts that they want. The good thing about these corporate structures is that they will always have access to the experts in taxes and corporate law to help them sort things out. With the experts on their side, there is really nothing that they cannot do.

More importantly, when you decide to get the help of the experts, you are not only lessening the taxes that you pay for, you are also making your company more cost-efficient. No matter what type of industry you may be in, there will always be a creative way out of the huge taxes that the government makes you pay. This is when the brilliant minds of experts in ta come in to save you.

From planning to consulting to directing all the necessary changes that need to be made, the calgary corporate accountants and laws in Calgary could definitely be of good use. All of these can be achieved through the right corporate planning. You’d be surprised at how much more efficient your company can be when it comes to managing costs and diverting funds.

Plan ahead and reap all the rewards after. You don’t have to be the expert yourself. You just have to find someone who can focus on making the savings happen while you continue to improve the services and products that you provide.

Amy William / February 14, 2015 / Accounting / 0 Comments

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

The Facts About EDS

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders, characterized by articular (joint) hypermobility, skin extensibility and tissue fragility. There are six major types of EDS. The different types of EDS are classified according to their manifestations of signs and symptoms. Each type of EDS is a distinct disorder that “runs true” in a family. This means that an individual with Vascular Type EDS will not have a child with Classical Type EDS. Individuals with EDS have a defect in their connective tissue, the tissue which provides support to many body parts such as the skin, muscles and ligaments. The fragile skin and unstable joints found in EDS are the result of faulty collagen. Collagen is a protein which acts as a “glue” in the body, adding strength and elasticity to connective tissue.

Symptoms

Clinical manifestations of EDS are most often skin and joint related and may include:

Skin: soft velvet-like skin; variable skin hyperextensibility; fragile skin that tears or bruises easily (bruising may be severe); severe scarring; slow and poor wound healing; development of molluscoid pseudotumors (fleshy lesions associated with scars over pressure areas).

Joints: joint hypermobility; loose/unstable joints which are prone to frequent dislocations and/or subluxations; joint pain; hyperextensible joints (they move beyond the joint’s normal range); early onset of osteoarthritis.

Miscellaneous/Less Common: chronic, early onset, debilitating musculoskeletal pain (usually associated with the Hypermobility Type); arterial/intestinal/uterine fragility or rupture (usually associated with the Vascular Type); Scoliosis at birth and scleral fragility (associated with the Kyphoscoliosis Type); poor muscle tone (associated with the Arthrochalasia Type); mitral valve prolapse; and gum disease.

Prevalence

At this time, research statistics of EDS show the prevalence as 1 in 5,000 to 1 in 10,000. It is known to affect both males and females of all racial and ethnic backgrounds.

Hereditary Patterns

The two known inheritance patterns for EDS include autosomal dominant and autosomal recessive. Regardless of the inheritance pattern, we have no choice in which genes we pass on to our children.

How is EDS Diagnosed

Diagnosis of EDS is based upon clinical findings and upon the family history. Since many patients do not fit neatly into one of the specific types of EDS, a diagnosis is often delayed or overlooked. Specific diagnostic tests are available for some types of EDS in which there is a known biochemical defect. Sometimes, a physician may perform a skin biopsy to study the chemical makeup of the connective tissue. The biopsy involves removing a small piece of skin, under local anesthesia. Physicians who are able to diagnose EDS may include medical geneticists, pediatricians, rheumatologists and dermatologists.

Treatment/Management of EDS

The gaping skin wounds, which are common in several types of EDS, should be approached with care. Proper repair of these wounds is necessary to prevent cosmetic disfigurement. Surgical procedures can be risky, as fragile tissues can unexpectedly tear. Suturing may present problems for the same reason.

Excessive sun exposure should be avoided by the daily use of sunscreen. One should avoid activities that cause the joint to lock or overextend.

A physician may prescribe bracing to stabilize joints. Surgical repair of joints may be necessary at some time. Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints. To decrease bruising and improve wound healing, some patients have responded to ascorbic acid (vitamin C) by taking 1 to 4 grams daily. Prior to starting a regimen such as this, it is imperative to consult with your physician for specific recommendations.

In general, medical intervention is limited to symptomatic therapy. Prior to pregnancy, patients with EDS should have genetic counseling. Children with EDS should be provided with information about the disorder, so they can understand why contact sports and other physically stressful activities should be avoided. Children should be taught early on that demonstrating the unusual positions they can maintain due to loose joints should not be done as this may cause early degeneration of the joints. Family members, teachers and friends should be provided with information about EDS so they can accept and assist the child as necessary.

Prognosis

The 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.

Victoria Hall / January 20, 2015 / EDS / 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

The Genetics & Molecular Biology Of EDS

What Is DNA?

The set of genetic instructions is on a very large and complex molecule called DNA. The DNA molecule is like a very long ladder. The backbones of the ladder are repeating sets of a sugar and a phosphate molecule. The rungs of the ladder are made up of a pair of molecules. Each is a chemical base attached to the sugar molecule on the backbone.

The Genetic Message 

The genetic alphabet is made up of four bases: Adenine, Thymine, Cytosine and Guanine. They are abbreviated A, T, G, and C. The code for the actual DNA instructions is the order of the bases as they are lined up on one side of the ladder. The lineup of bases on the other side of the ladder is the complementary strand. To keep the backbones of the DNA molecule even, an A base on one side always pairs with T base on the other side, and G always pairs with C. The complementary bases keep the DNA molecule even and are critically important in allowing the DNA molecule to copy itself. The DNA must copy (replicate) itself before the cell divides so that each new cell can have a complete copy of the message. The first thing the DNA does to replicate itself is to separate down the middle. This splits the paired bases and gives two half-ladders. The exposed bases on each half-ladder creates a pattern for the two new identical copies. Each exposed base now pairs with a new base and new backbones are constructed. Our English language makes words by stringing letters together. Genetic words are three genetic letters (bases) long. Each genetic word tells the cell to get a molecule called an amino acid. Our English language makes sentences by stringing words together. Genetic sentences are made by stringing different amino acids together; these make protein molecules. There are only 20 amino acids, but by stringing them together in different combinations, a limitless number of different proteins can be made. These proteins are the building blocks and workhorses of the cell. They help the cells carry out the instructions contained in the DNA molecule.

What Are Genes?

Genes contain the instructions that tell cells what to do. Basically each gene is a genetic sentence that produces a different protein.

What Are Chromosomes?

Chromosomes are genetic books. Each one is a very long strand of DNA that contains hundreds of genetic sentences (genes). Like English sentences, genes are meant to be read in a certain direction, and they are arranged in a specific order. Unlike the organization of sentences in a book, the arrangement of genes on the chromosomes do not have to make a sensible story. For example, a gene that produces a protein that influences hair color may be next to a gene that helps the cell produce energy. The place where a given gene lies along the length of a chromosome is its genetic LOCUS. Just as books come in different sizes and thickness, chromosomes can also have different lengths and shapes.

Pairs Of Genes, Pairs Of Chromosomes

Chromosomes (and genes) come in pairs. The two members of each pair of chromosomes are called homologs. One homolog came from your father and the other came from your mother. Humans have 23 pairs of chromosomes. Twenty-two of these pairs are numbered for identification. They look the same in males and females and are called autosomes. The 23rd pair is called the sex chromosomes because they determine the sex of the child. Females have two identical sex chromosomes call X chromosomes. Males have and X and a Y chromosome. The presence of the Y chromosome determines maleness.

Different Traits Are Determined By Gene Pairs

A person with similar genes is homozygous at that locus. One with different genes is heterozygous for that locus. The ways in which the genes are homozygous or heterozygous determine the different types of inheritance. The three main types of inheritance are autosomal dominant, autosomal recessive, and sex-linked recessive.

Reading The Genetic Code 

Until very recently, it was next to impossible to decode the genetic messages. The human DNA message is about 3 billion bases long. There are approximately 100,000 genes, so each gene has an average of 30,000 bases coding for 10,000 amino acids each.

Restriction Enzymes 

In the early 1970’s, scientists discovered that bacteria had enzymes that would attack foreign DNA and cut the DNA up into little pieces. What was interesting was that these enzymes were restricted to a specific sequence of the genetic alphabet to make the cut. This is why they are named restriction enzymes (RE). There are over 200 restriction enzymes known and many cut the DNA in different places.

Genetic Probes

A genetic probe is a piece of DNA that matches the message you are trying to find. This probe also may be labeled with a radioactive chemical.

Molecular Genetics 

The technique for finding genes goes something like this. First you cut the DNA with a restriction enzyme. All the pieces of DNA after one of these cuts are called restriction fragments. Next you separate all the cut DNA by the size of the resulting pieces. If you put the DNA in a gel (like unflavored Jello) and pass an electric current through the gel, the DNA will migrate in the direction of the current. The smaller pieces will migrate further than larger pieces. Next you transfer the DNA to a piece of filter paper, like a coffee filter [it is easier to work with paper than with Jello!!]. Next you use the radioactive labeled probe to find the restriction fragment(s) that match the probe. The probe will attach to the restriction fragment(s) it matches. Finally, you can see where the probe attached to the DNA on the paper by exposing it to a sheet of unexposed X-ray film. This is autoradiography. You can estimate the size of DNA fragments by how far they have migrated. Small pieces move farther than bigger pieces. All the DNA fragments revealed by this technique are called RFLPs, which stand for Restriction Fragment Length Polymorphism.

Family Studies 

Frequently we do not have a probe that is complementary to the DNA of interest. Instead we can use a piece of anonymous DNA — this is one where the message is known and that message doesn’t mean anything. If we take DNA from family members with a known genetic condition, we can apply these techniques to look at the RFLPs in that family. If one RFLP is consistently found in all family members with the same condition, we have good evidence that RFLP either contains or is very close to the gene causing the condition.

Autosomal Dominant Inheritance 

Genes are the basic unit of inheritance. They provide the instructions for growth and development of the single cell of a fertilized ovum into the complex structure of a baby. Many continue to provide instructions for the production of proteins needed for bodily functions throughout a person’s lifetime. Genes are strung together like beads on a string and packaged into individual chromosomes. Chromosomes come in pairs; with one coming from an individual’s mother and the other from the father. One pair of chromosomes is called the sex chromosomes, since they determine the sex of the individual; the other 22 pairs of chromosomes are called autosomes.

Since our chromosomes come in pairs, we have two copies of all of our genes. The two copies in a pair of genes may or may not have the same code. A gene that is expressed regardless of the code in the other gene is said to be dominant. An autosomal dominant gene is one carried on one of the 22 pairs of autosomes which means that males and females with the gene are equally likely to pass it on to male or female offspring.

A person who has an autosomal dominant form of EDS (Classical, Hypermobility, Vascular, and Arthrochalasia types) generally has one gene for EDS and one normal gene in one pair of genes. There is a 50 percent chance that the affected parent will contribute the EDS gene and a 50 percent he or she will contribute the normal gene.

There can be variation in the expression of a dominant gene even within the same family. In other words, the gene may cause a profound loss for an individual and only a mild to moderate loss for that individual’s child. Another phenomenon that is seen with some dominant genes is non-penetrance. This means that there is no detectable evidence that an individual with a dominant gene has the gene. When the gene is non-penetrant it appears that the gene has skipped a generation.

Autosomal Recessive Inheritance 

A person with an autosomal recessive EDS (Kyphoscoliosis and Dermatosparaxis types) would have to have two recessive genes for EDS in that particular pair of genes. A person with a normal gene and an EDS gene would not have a EDS, but would be considered a carrier. Generally the EDS gene has been passed down through the carrier’s family for generations. A carrier has no way of knowing that he or she has an EDS gene until having a child with EDS. Then it becomes apparent that the individual and the individual’s spouse each is a carrier. All of us have several recessive genes, each of which could cause significant problems for our children if it happened to get paired up with the same recessive gene from our partner.

For example, if the mother and father are carriers of a gene for EDS, it can be designated with an r. They also have one normal gene which is designated with an R. When they have a child each will pass on one of those genes. If they both pass on the R, the child will have two normal messages, not have EDS and cannot pass the EDS gene to his children. There is 1 chance out of 4 or a 25% chance for the child of two carriers to receive both normal genes. If one parent passes on the R and the other the r, the child will have one normal message, not have EDS, and be a carrier like the parents There are 2 chances out of four, or a 50% chance of the child of two carriers being a carrier also. If both parents pass on an r, the child will have no normal message and will have EDS. There is 1 chance out of 4 or a 25% chance that the child of two carrier parents will receive both EDS genes and have EDS. The chance of carrier parents having a child with EDS is the same with each pregnancy. If they have one child with EDS, it does not mean that their next child will not have a EDS also. The genes are passed on in a random manner and what has already happened in existing offspring has no influence on future offspring.

Regardless of the type of EDS, parents should never feel guilt toward themselves for passing along an EDS gene, this can not be controlled nor predicted in each pregnancy.

Amy William / January 17, 2015 / EDS / 0 Comments

PHARMACOLOGICAL CONSIDERATIONS In EHLERS-DANLOS SYNDROME

EHLERS-DANLOS SYNDROME  A BRIEF OVERVIEW

EDS is a genetic defect in the collagen molecule itself.  An inherited connective tissue disorder characterized by joint hypermobility, dislocation/subluxations, bleeding, bruising, dermal hyperelasticity, and widespread tissue fragility, skin tearing & poor wound healing.  Unlike Lupus, EDS is not an antigen/antibody problem.  EDS is gene mutations effecting the structure or assembly of different collagen’s.  The cross-linking of the collagen fibrils is thought to be defective. EDS is a very painful & debilitating syndrome. THE SYMPTOMS BELOW OCCUR IN THE NORMAL POPULATION  and are not exclusive to EDS, however due to the increased medication induced bleeding tendencies in the normal population, individuals with EDS may have a higher incidence of pharmacological considerations, especially in Vascular Type EDS.

PAIN & EDS

Nov. 1997, Vol. XII, Number 4 of “Loose Connections”, the official communication link of the EDNF reprinted by permission of Elsevier Science, Inc.  Journal of Pain & Symptom Management,Vol.14,No.2,pp.88-93 Copyright 1997 by the Cancer Pain Relief Committee”. “Chronic Pain is a Manifestation of the Ehlers-Danlos Syndrome”.

Pain and EDS is a simple summary of the seven most striking points about Ehlers-Danlos Syndrome pain.

  1. Moderate to severe pain of diverse distribution is a common every day occurrence, starting early in life and worsening over time.
  2. Pain with EDS is complexly individualized.
  3. EDS is a very painful and debilitating syndrome.
  4. Most EDS patients, but not all, have (at some point) taken some type of medication. Joint pain and instability are the primary cause for use of pain medications.
  5. Chronic dislocation and subluxations can be very painful.
  6. Pain Insomnia has been widely reported by most EDS sufferers, (46)of the (51) individuals interviewed indicated they had chronic pain over the last 6 months or longer.
  7. Areas of pain reported =A total of thirteen different `principal pain locations’ were identified. The elbow, shoulders(1 or both), hands, knees, spine, frequent headaches, stomach aches & Continuous pain in extremities, ankles, feet, toes & hips. The Pain was described as aching, sharp, throbbing or burning & significant enough to experience dysfunction in sleep, physical activity & sexual activity.

LONG TERM USE & LONG ACTING MEDICATION

Pharmacologically, pain can be treated with several different types or combinations of medication, analgesics, opiates, anti-inflammatory drugs and/or antidepressant therapy. It is important to take all medication as directed and on time. Pain is much easier to manage (with less medication)at the first sign of discomfort than it is to treat  or manage ‘out of control’ pain.

Chronic illness sometimes forces the medical profession to be creative in medication management. Difficulty swallowing, Allergies and trauma to soft tissue from injections and/or needle pricks, as well as remembering to take the medication on time makes long-acting medication ideal for the EDS patient. Low dose titration of pain medication allows the body a chance to ‘adjust’ to the introduction of medication. It allows for some autonomy and the lowered incidence in nausea and other side effects like drowsiness, plus, the effective relief of pain decreases patient fears, promoting understanding of the medications, leading to better medication compliance and more comprehensive pain control.

There are many different opiates, analgesics and pain medication that working together with your doctor you should be able to find pain relief that fits your lifestyle.

DISPELLING MYTHS ABOUT ADDICTION & CHRONIC ILLNESS 

MOST pain medications and other drug classifications can create TOLERANCE requiring an adjustment (increase) dosage. This IS NOT ADDICTION. Addiction is misuse or abuse of a drug, usually to obtain a `high’. When  your pain becomes intolerable & the doctor increases your medication, this DOES NOT make you a ‘drug addict’. In fact, most people in pain do not reach a

`high’, just pain control. If your EDS were to `magically’ disappear you would be tapered off the medication & be drug free again. Some of the same holds true to other medications like Steroids & some Antidepressants. Pain can cause nausea, anxiety, agitation, depression, feelings of isolation, hopelessness & helplessness. Good pain control can give you quality of life and increase functioning. Pain Control Clinics and knowledgeable physicians can help you obtain the best medication regime for your pain level and lifestyle. You do not have to suffer in pain.

NO MEDICATION  SHOULD BE  STOPPED ABRUPTLY WITHOUT  FIRST CONSULTING  YOUR DOCTOR

DRUGS THAT INCREASE BLEEDING (Most commonly, but not limited to Vascular EDS)

These drugs increase the risk of prolonged bleeding & other side effects in the normal population and are not exclusive to EDS. Many drugs have aspirin in them, this may increase your risk of bleeding or bruising. You can ask if the same drug comes mixed with Tylenol instead, for example; Percocet instead of Percodan.

NSAIDS NAPROSYN
HEPARIN TORADOL
IBUPROFEN ANAPROX
SEPTRA -DS CORTICOSTEROIDS
ASPIRIN BACTRIM- DS
FIORINAL PERCODAN
MOTRIN PREDNISONE

MIDOL …these are just a few, read your packet inserts, talk to your doctor or pharmacist about potential drug interactions or bad combinations. BE INFORMED!!!

TYLENOL taken in even moderate doses over a long period of time can cause liver damage.

ANTIBIOTICS can irritate a pre-existing ulcer. Use with caution especially in someone with EDS with preexisting Gastrointestinal problems.

IV’s-Should NEVER be FLUSHED with HEPARIN…NORMAL SALINE  works just aswell, without, the added side-effects & potential to increase clotting time.

Xylocaine can be given to numb the site before attempting  to `find a vein’. Some EDS patients DO NOT respond to Local Anesthesia. NEEDLE GAUGE: REGULAR IV’s can be as small as 25.

Blood transfusions or blood products can be given through a 22 Needle Gauge.! You have to speak up before they stick you or it’s too late and you have probably just received ‘normal protocol’ & unnecessary PAIN!

Whole units of blood can be  put through a warmer , unless contraindicated, ask because they probably won’t think of it.

ALLERGIES- A  COPY OF ALL ALLERGIES TO MEDICATION & FOODS or  adverse reactions to certain drugs SHOULD BE  WITH YOU! This should be part of your

MEDIC ALERT  ID- This helps the medical profession help you! List  your diagnosis and all allergies, medications and doctors.

IN SUMMARY 

Pharmacological considerations in people with Ehlers-Danlos Syndrome include ,but are not limited to, several types of drugs that can increase bleeding in the normal population and those EDS sufferers with a pre-existing tendency to bleed must be acutely aware of their current drug regime. It is important, with any chronic illness, to carry copies of, as well as information about any, ALLERGIES (food too), medications or medication interactions. It is important to tell your doctor ALL the medications you take, even over-the-counter drugs, Aspirin/Tylenol/Advil. Always ask if your ‘new’ medication contains Aspirin or is compatible with anything else you may be taking. It is OK to ask for the smallest gauge needle to avoid soft tissue injury. Chronic  pain is a clinical manifestation of Ehlers-Danlos Syndrome. The pain is complexly individualized, diverse in its location & intensity. EDS pain commonly requires intervention by trained professionals, Pain Control Clinics &/or  doctors who are educated and/or willing to learn about this complex syndrome. Pain should be reported immediately. Scale your pain so the doctor can understand how much pain you are in. PAIN-SCALE=(1-5) or (1-10) the highest number being INTOLERABLE. You do not have to live in pain. Pain Clinics, qualified knowledgeable physicians & pharmacists can help you find the best medication regime that fits your lifestyle. Remember your pharmacist is a knowledgeable resource.

Amy William / January 15, 2015 / PHARMACOLOGICAL CONSIDERATIONS / 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

Clinical And Genetic Features Of Ehlers-Danlos Syndrome Type IV, The Vascular Type

Abstract

Background

Ehlers-Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented.

Methods

We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients.

Results

Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1.

Conclusions

Although most affected patients survive the first and second major complications, Ehlers-Danlos syndrome type IV results in premature death. The diagnosis should be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture. (N Engl J Med 2000;342:673-80.)

The clinical diagnosis of Ehlers-Danlos syndrome type IV, the vascular type, is made on the basis of four clinical criteria: easy bruising, thin skin with visible veins, characteristic facial features, and rupture of arteries, uterus, or intestines. The diagnosis is confirmed by the demonstration that cultured fibroblasts synthesize abnormal type III procollagen molecules or by the identification of a mutation in the gene for type III procollagen (COL3A1). Hypermobility of large joints and hyperextensibility of the skin, characteristic of the more common forms of Ehlers-Danlos syndrome, are unusual in the vascular type. Ehlers-Danlos syndrome type IV, an autosomal dominant disorder, is uncommon (the precise incidence and prevalence are not known), and in part because of its rarity, the diagnosis is often made only after a catastrophic complication or at postmortem examination. As is often the case with rare genetic disorders, physicians’ unfamiliarity with the condition may compromise care. Although there are many brief clinical descriptions and case reports focusing on the molecular genetics, the scope of the clinical complications, the results of therapeutic intervention, and information about survival are not readily available. To provide the basis for a better understanding of the course of the disorder and for more informed counseling of patients and their families, we studied the clinical records of 220 index patients, in whom the diagnosis was confirmed by biochemical analysis, and 199 of their affected relatives.

Methods

Study Subjects

The 220 index patients included all 217 patients whose cultured fibroblasts synthesized abnormal type III procollagen molecules who were evaluated in Seattle between 1976 and 1998 and 3 additional patients who were evaluated biochemically in Zurich, Switzerland, before 1990. We personally examined members of 13 families in Seattle and 3 families in Zurich. From the medical records of each index patient we determined the reasons for the initial referral to a physician and assessed the medical history, family history, physical findings, and when included, autopsy results.
We used three criteria to designate 199 relatives of the index patients as having Ehlers-Danlos syndrome type IV: cultures of dermal fibroblasts synthesized abnormal type III procollagen molecules in the case of 44 relatives; a familial molecular genetic abnormality was identified in the DNA of 35 relatives; and evidence in the family-history portion of the index patient’s records indicated that the relative had had an arterial rupture, dissection, or aneurysm, bowel perforation, or organ rupture in the case of 120 relatives. Additional clinical data were provided for the first two groups of relatives at the time of testing; only data in the medical records of the index patient were available in the case of the remaining relatives.

Relatives were classified as unaffected if they were reported by a physician to be unaffected, if the results of biochemical or molecular genetic studies excluded the diagnosis, or if they had not had a major complication by the age of 50 years. We identified 462 relatives with a 50 percent risk of inheriting the condition on the basis of family-history data, of whom 238 (51.5 percent) were affected. Forty of the 224 apparently unaffected relatives were younger than 16 years of age and had not been tested, so their status could not be confirmed. These data suggest that most affected members of these families were identified.

From available medical records of the index patients and some of their relatives, we determined the number and type of medical or surgical complications, the ages at which they occurred, the cause of and age at death, reported birth defects, and identified complications of pregnancy. The age at testing (i.e., ascertainment) in the index patients was the age at which we confirmed the diagnosis. For their affected relatives, the age at ascertainment was the age at which we identified them with the use of biochemical or molecular genetic studies, their last known age, or their age at death, as recorded in the family history. The age at ascertainment was known for 374 of the 419 subjects (207 index patients and 167 relatives) and ranged from 1 to 78 years. The index patients were identified at a younger age than were their affected relatives, as would be expected when family histories are used to identify affected members of prior generations. Except for the study subjects who lived in our local communities, we did not follow most subjects after the diagnosis of Ehlers-Danlos syndrome type IV.

Seventy percent of the index patients (154 of 220) were referred for evaluation after a major event. Sixty-six index patients who had had no complications had one or more physical findings consistent with the diagnosis (characteristic facial features, thin skin with visible veins, easy bruising, and increased joint mobility of the hands) that led to the evaluation. Thirty-two of these 66 patients also had affected relatives who had had complications.

Biochemical and Molecular Studies

Dermal fibroblasts were obtained from the subjects and cultured, and the synthesis of type III procollagen was studied as described previously. For the molecular studies, RNA and DNA were extracted from cultured fibroblasts, and complementary DNA was synthesized by reverse transcription from RNA. Overlapping fragments of complementary DNA were amplified by the polymerase chain reaction and analyzed by electrophoresis on polyacrylamide gels to identify insertions or deletions or by single-strand conformation polymorphism analysis to detect point mutations in the coding sequence. Abnormal fragments were sequenced by the dideoxy chain-termination method with T4 polymerase (Sequenase, U.S. Biochemicals, or Prism model 310 genetic analyzer, Applied Biosystems). All mutations were confirmed by sequence analysis or restriction-enzyme digestion of genomic DNA.

Statistical Analysis

We used a two-sample t-test, assuming that variance was unequal, to compare the mean age at ascertainment and at the time of complications in the index patients and their affected relatives. We used life-table methods to estimate survival (SPSS statistical software, version 7.5) and included the age at death (including information on two index patients whose deaths were apparently unrelated to any complication of Ehlers-Danlos syndrome type IV) or the last known age of each living subject. We constructed a normal curve from the 1994 age-specific death rates from the Division of Vital Statistics of the Centers for Disease Control and Prevention. We compared Kaplan-Meier survival curves for the index patients and their relatives using a log-rank statistical analysis (SPSS software, version 7.5). We also used Kaplan-Meier analysis to calculate survival free of a first complication for the index patients (SPSS software, version 7.5) by plotting the expression [1-(cumulative survival)] against age, with survival defined according to the age at the time of the first complication.

We computed standardized incidence ratios to compare the rate of birth defects in our affected subjects with the rate in the general population. The ratios and 95 percent confidence intervals were calculated on the assumption that the values followed a Poisson distribution. All P values were two-sided.

Results

Survival

A total of 131 subjects died: 26 index patients and 105 relatives. The overrepresentation of relatives probably reflects our method of ascertaining their disease status by using the records of younger index patients and the clinical criteria for diagnosis and inclusion. The median survival for the entire cohort was 48 years. The age at death ranged from 6 to 73 years. The median survival of the index patients was longer than that of their affected relatives. It is not clear whether this difference reflects the different age distributions in the two groups or recent improvements in medical care.

Causes of Death

Most deaths resulted from arterial dissection or rupture. Of 103 deaths caused by arterial rupture, 78 involved thoracic or abdominal vessels and 9 resulted from central nervous system hemorrhage; the artery was unspecified in the case of 16 deaths. About half the remaining deaths resulted from organ rupture; bowel rupture and sepsis accounted for 8 percent of all deaths.

Medical and Surgical Complications

At the time of ascertainment, 287 of the 419 subjects (68 percent) had had a single complication (defined as arterial dissection or rupture, spontaneous bowel perforation, or organ rupture) and 86 (21 percent) had had more than one. Among the index patients the risk of a medical or surgical complication was 25 percent by the age of 20 years and greater than 80 percent by the age of 40 years. To determine how often a complication led to death, we assessed the outcome of first and second complications for the index patients. We excluded relatives from the evaluation because their medical histories were less complete or were unavailable. Among 220 index patients, 154 had had at least one complication and 18 (12 percent of those with complications) died after the first event. The likelihood of death was greatest after organ rupture (45 percent) and least after bowel rupture (2 percent). The average age at the time of a first complication was 23.5 years, with rupture of the gastrointestinal tract likely to occur at an earlier age than arterial rupture. Fifty-two of the 136 index patients who survived a first complication had a second recorded complication, which was fatal in 6 (12 percent). The relative frequencies of arterial complications and of gastrointestinal complications were similar for the first and second complications. The type of second complication did not reflect the nature of the first complication .

Arterial Complications and Surgical Outcome

In the entire cohort of 419 subjects, there were 272 identified arterial complications. About half involved the thoracic or abdominal arteries, and the rest were divided equally between those in the head and neck and those in the limbs. Forty-three subjects had 44 arterial complications of the central nervous system between the ages of 17 and 65 years (mean age, 32.8); 17 of these subjects have been described previously. The most common nonlethal central nervous system events were fistulae involving the carotid artery and cavernous sinus (10 subjects), carotid-artery dissection (8), aneurysm (5), and rupture (8).

We had documentation that 98 subjects had undergone an invasive evaluation procedure or surgery: 29 had undergone angiography, 1 of whom died during cerebral studies, and 69 had undergone surgery, 28 of whom died. Among the 28 who died during or after surgery, the underlying diagnosis was not known at the time in most, and often the patient was moribund even before surgery.

Gastrointestinal Complications and Surgical Outcome

Most of the identified bowel complications (62 of 87) in the index patients and relatives affected the colon, commonly the sigmoid colon (in 29 subjects). Perforation of the small bowel (seven subjects) and gastric perforation (two subjects) were uncommon. Ten deaths were recorded as resulting from rupture of the gastrointestinal tract. Tissue fragility and poor wound healing contributed to surgical complications, death, or both. Dehiscence of the wound, evisceration, hemorrhage of abdominal vessels, fistulas, and adhesions were all described. Recurrent bowel rupture was reported in 15 subjects and occurred between 2 weeks and 26 years after the first event.

Spontaneous bowel perforation was usually treated by partial colectomy. In the case of 42 subjects who underwent partial colectomy, medical records indicated that partial resection was followed by colostomy in 26 subjects and that immediate end-to-end reanastomosis was performed in 8. Closure of the colostomy and reanastomosis of the bowel were successfully performed between one month and one year after initial repair in 22 subjects. Seven of these subjects had a second bowel perforation, whereas at least six survived with no recurrence for an average of 6 years (range, 3 to 16). In the eight subjects who underwent an initial end-to-end reanastomosis, perforations recurred in five within 1 to 22 years. Among the three remaining subjects, one died of peritonitis, one had an abdominal hemorrhage that led to splenectomy, and there was no information available for the third.

Total colectomy was performed in four subjects after repeated perforations. All were younger than 25 years of age. The duration of follow-up ranged from one to nine years, and there was a single death from arterial rupture during this period.

Outcome of Pregnancy

Eighty-one of the women with Ehlers-Danlos syndrome type IV had had a total of 183 pregnancies, with 167 deliveries of live-born infants at term, 3 stillbirths, 10 spontaneous abortions, and 3 voluntary terminations. Twelve women died during the peripartum period or within two weeks after delivery (five of uterine rupture during labor, two of vessel rupture at delivery, and five in the postpartum period after vessel rupture). Five of these pregnancy-related deaths have been reported previously. There were five pregnancy-related deaths among the 81 women who had been pregnant once, three among the 53 who had been pregnant twice, two among the 24 who had been pregnant three times, two among the 13 who had been pregnant four times, and no deaths among the 6 women who had been pregnant five times, the 2 who had been pregnant six times, or the 1 who had been pregnant seven times. The three women who underwent voluntary termination of pregnancy were excluded from the analysis.

Congenital Defects

Two congenital defects were reported more frequently than expected among the subjects: club-foot (in 41 subjects, 24 male subjects and 17 female subjects; rate in the general population, 20 per 10,000; P<0.001) and congenital dislocation of the hip (in 8 subjects; rate in the general population, 7.3 per 10,000 [Botto LD: personal communication]; P<0.001). A total of 12.4 percent of index patients (21 of 169) were born prematurely, as compared with 11 percent of the U.S. population.

Correlation between Genotype and Phenotype

We identified the causative mutations in the COL3A1 gene in 135 index patients. Four mutations led to the deletion of multiple exons (2 of which have been reported previously, and 41 led to the skipping of a single exon. One mutation (IVS24+1G-to-A) led to the skipping of exon 24 in seven unrelated index patients. Four index patients had splice-site mutations with complex splicing outcomes and multiple messenger RNAs. In a single index patient a 10-bp deletion in the acceptor site of intron 29 led to the presence of a cryptic site within exon 30 and to the deletion of three amino acids from the triple helix. In the remaining 85 index patients, 73 different point mutations led to the substitution of some other amino acid for glycine throughout the triple-helical domain. A number of mutations — G16S (seven families) and G82D, G373R, G385E, G415S, G499D, and G1021E (two families each) — were identified multiple times in unrelated index patients. We discerned no correlation between the nature or location of the mutation and the type or frequency of major complications.

Discussion

We identified 220 patients whose cultured dermal fibroblasts synthesized abnormal type III procollagen molecules, a finding that is diagnostic of Ehlers-Danlos syndrome type IV. From the family histories of these index patients we identified 120 affected relatives on clinical grounds, and we identified an additional 79 relatives as affected on the basis of diagnostic biochemical or molecular genetic studies. The value of the data on survival, outcome of complications, and age at the onset of complications depends on the extent to which this large group represents the population of people with this uncommon disorder. The clinical diagnosis of Ehlers-Danlos syndrome type IV rests on the finding of at least two of four diagnostic criteria (thin, translucent skin; arterial, intestinal, or uterine rupture; easy bruising; and a characteristic facial appearance), but laboratory studies are necessary for confirmation.

In our study, the diagnosis was confirmed biochemically in all the index patients, so the clinical significance and applicability of the findings in this study depend on whether we were referred a representative group to study. The 220 index patients fell into three groups: 154 were referred for evaluation after a major complication, 32 were evaluated because they had a family history strongly suggestive of Ehlers-Danlos syndrome type IV and they had physical findings characteristic of the condition but no known complications, and 34 were evaluated because they had physical findings of the diagnosis but no affected relatives. The estimated median survival did not differ significantly among the index patients, the affected relatives of index patients who had had a complication, and the affected relatives of index patients who had not had a complication (data not shown), suggesting that the groups were similar. The nature, type, and location of mutations were also similar among the three groups. Thus, although the reasons for evaluation varied, it seems likely that the group as a whole was made up of people at different points in the evolution of the condition and did not represent different subgroups of those with Ehlers-Danlos syndrome type IV. Nonetheless, our results pertaining to the natural history of the disease, the age at the time of a first complication, and the incidence and causes of death may be most relevant to patients identified in a similar manner.
In this population, survival was shortened, largely as a result of vascular rupture. The age at death ranged from 6 to 73 years, with a median life span of 48 years. The median survival was longer for the index patients than for their relatives, but it was not clear whether this difference reflects better medical care or differences in the age distributions of the groups. Major complications were uncommon in childhood, but 25 percent of the index patients had had medical or surgical complications by the age of 20 years, and more than 80 percent had had such complications by the age of 40 years.

In this group of patients, rupture of any artery into a free space is life-threatening and requires immediate intervention, even though the tissues are friable and repair is often difficult. Rupture into a confined space may be sealed because of tamponade, however, and in such cases, surgical intervention may be deleterious. Although a preexisting aneurysm could occasionally be documented, usually either studies had not been done or no aneurysms were documented. Whether there is a role for the repair of unruptured aneurysms in patients with this syndrome is not clear.
Although arterial tears are considered the hallmark of Ehlers-Danlos syndrome type IV, about 25 percent of all complications in this group affected the gastrointestinal tract. Prompt surgical intervention was usually crucial in the treatment of bowel rupture, and colostomy was the preferred treatment. Bowel continuity was restored with little difficulty in most cases. Treatment of bowel perforation with end-to-end reanastomosis after partial colectomy was associated with a higher risk of both immediate failure and later complication than was treatment with colostomy. Because the sigmoid colon is a frequent site of rupture, removal of the distal colon may decrease the risk of recurrence.

Women with Ehlers-Danlos syndrome type IV have an increased risk of complications of pregnancy as well as a 50 percent risk of having an affected child. In one series, there were no deaths or clinically significant complications during more than 20 pregnancies in eight women with COL3A1 mutations, whereas other studies have reported pregnancy-related deaths and complications in such women. If the 20 women (5 of whom died of pregnancy-related causes) whom we described previously are excluded from the analysis, the mortality rate among women who became pregnant was 11.5 percent (1 death per 23 pregnancies). Women with Ehlers-Danlos syndrome type IV who become pregnant should be considered at high risk and should be followed at specialized centers. Although several pregnant women died of uterine rupture at term, we do not know whether the use of elective cesarean section would decrease mortality.

Fibroblasts from all the index patients synthesized abnormal type III procollagen molecules, and to date we have identified causative mutations in the COL3A1 gene in more than half. We did not find that different rates of arterial or gastrointestinal complications were associated with different types of mutation or with specific mutations. Mutations that affect the structure of type III procollagen may produce a milder form of disease than that in most of the patients and families we studied, and the life span of persons with such mutations can approach normal, as was true in one previously described family included in our study. There is no evidence of heterogeneity of genetic loci in Ehlers-Danlos syndrome type IV, and the only specific correlation between genotype and phenotype recognized to date is with minor phenotypic findings. The effects of null mutations have yet to be established, although our unpublished evidence suggests that they can cause severe disease.

Although no specific therapies delay the onset of complications in patients with Ehlers-Danlos syndrome type IV, knowledge of the diagnosis may influence the management of surgery, pregnancy and reproductive counseling, and major complications. The diagnosis should be considered and biochemical evaluation performed in young people with unexplained bowel or arterial rupture, especially those with a family history of similar events.

Supported in part by funds from the National Institutes of Health (AR 21557).

We are indebted to the families that participated and their physicians for providing samples and clinical summaries, to Barbara Kovacich for help with the preparation of the manuscript, and to Drs. Beat Steinmann and Richard Gitzelmann for their thoughtful comments on the manuscript.

Victoria Hall / January 11, 2015 / Genetic Features / 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