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. 

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. 

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. 

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:

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  

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  

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.

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. 

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  

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  

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. 

INTRODUCTION

What was originally described by Weber (99) as Ehlers-Danlos syndrome (EDS) is in fact a hetero­geneous group of clinical syndromes, often with a family history. Ehlers, a Danish dermatologist (26), described a 21-year-old patient who bruised easily, and Danlos, a French physician (21), reported a patient who did not bruise but who had extensive scarring of the skin. Both patients had hypermobile joints and hyper extensible skin (cutis laxa). The first report probably dates from 1682 when van Meekeren (95) described a patient with “extraordinary elasticity of the skin” – It was, however, not until 1960 that it was recognized that some patients with this syndrome had severe vascular problems, in some cases even with spontaneous rupture of non-aneurysmatic arter­ies and sometimes death (65). Until now there are at least 12 types of EDS described with various genetic characteristics, biochemical defects, and clinical pres­entations (3, 51, 67). EDS type I (gravis or classic) and above all EDS type Iv (arterial or ecchymotic form) are of interest to surgeons as the patients often present with vascular catastrophes. Another mani­festation is gastrointestinal, with spontaneous bowel rupture being a severe outcome (1, 7, 91). A few patients have the combination of bowel perforation and vascular symptoms (15, 40, 80, 82, 87). There seems to be an increased risk of congenital heart disease (58, 64, 90, 97). Not only is there over-representation of aneurysms in the younger age groups, but stenoses have also been reported in the pulmonary arteries (53, 90).

A great step forward in the understanding of the EDS type IV was taken when Pope et al. (69) described a collagen defect as the molecular basis for the disease. Type III collagen (there are at least 13 different types of collagen) is reduced, this collagen being responsible for the tensile strength of arteries. There are several mutations which interfere with various steps in collagen production, which may in part explain the many variations in symptomatology of patients with EDS. New mutations do occur which explains why several cases lack a family history. His­topathologically, the arterial media is thin and the elastic fibres fragmented. For biochemical and genetic details readers should refer to review articles (3.48).

The minimal overall incidence of all types of EDS is 1/150000 (6), which is probably an underestimation because of mild undiagnosed cases. Between 3% and 5% of all are the severe type IV.

Fortunately, this form of EDS is rare but this leads to the problem of awareness and what to do when the patients present; this is true in elective surgery and even more in emergencies. The aim of this review therefore is to summarize our knowledge from a vascular surgical point of view and give some guidelines about how to act when the patients with EDS type IV present.

PATIENTS 

A review of published reports has disclosed 112 patients with the probable diagnosis of EDS type IV, among whom severe vascular complications have been reported and for whom enough details are given to make an analysis possible (2, 4-8, 10-20.22-25, 28-41,43,45-52,54-57, 59-61, 63, 65-68, 70-72, 74-89,92-94, 96,98, 100, 101). There are further patients with serious vascular complications that are men­tioned briefly in papers on genetics and molecular biology but for whom the clinical information is insuf­ficient (46).

There were 61 female patients with a median age of 28 years (range 11-61) and 51 male patients aged 25 years (10-54) at the time of the case report. In 26 patients the familial background was not reported, in 56 there were one or more relatives with EDS, and in 30 a family history of EDS was denied. A total of 96 (85%) had skin symptoms. in eight patients this

©1996 Scandinavian University Press. ISSN IIO2-4151

Table I. Arterial symptoms in 112 patients with EDS

                                                                                           Number of patients                                 Percent of all patients
With each symptom                                 with each symptom

Arterial aneurysm (12 aortic)                                                                    54                                                      50

Nonaneurysmatic arterial rupture                                                                 42                                                      38

Carotid cavernous fistula                                                                               27                                                      24

Gross haematoma (including retro peritoneal, bowel)                                   21                                                      19

Surgical bleeding                                                                                            18                                                      17

Arterial dissection (12 aortic)                                                                        14                                                      13

Aneurysm rupture                                                                                         10                                                        9

False aneurysm                                                                                                6                                                        6

AV-fistula                                                                                                        3                                                        3

Coronary aneurysm                                                                                         2                                                        2

was denied, and in eight there was a lack of information about the skin. The most common skin symp­toms were bruising (71%), followed by thin transparent skin (51%) and cutis laxa (49%). Many had scars of varying ages (30%). Only 16 had no joint symptoms, in 13 patients no report was given, and in the remainder there were varying degrees of hyper­mobility (75%), in 18 with a tendency to luxation. The hypermobility was often mild and localized to finger joints.

In the previous medical history quite a few patients had undergone abdominal, hernia, and gynecological operations without any problems being reported. Others had had severe problems with bleed­ing, ruptures, and friable tissues both in hernia sur­gery and during delivery. Nine of the patients were operated on for spontaneous rupture of the colon. Some patients presented with an acute abdomen with intense pain, but often without positive findings at various investigations. They were often misdiagnosed as acute pancreatitis, for example.

VASCULAR PROBLEMS

All kinds of vascular problems indicating fragile ves­sels have been reported (Table I). The high incidence of spontaneous carotid cavernous fistulas is remark­able, otherwise a rarity. Aneurysms developed at all locations in large and medium sized arteries and often multiple aneurysms were present in one patient. False aneurysms were also seen after minor trauma. Spon­taneous rupture of vessels with bleeding was common, both from aneurysmal as well as non-aneurysmal arteries. Development of a large haematoma after rupture of small vessels was often seen in the thigh, in the popliteal fossa and in the shoulder region. Varicose veins were common. In many of the patients there was extensive bleeding, particularly during rela­tively “simple” operative procedures because of extremely friable vessels.

 Table II. Cause of death in patients with EDS (56 deaths of 112 patients; 50%)

Cause                                                                                                      No. (%) of patients

_________________________________________________________________

Non-aneurysmal arterial rupture                                                            32            (57)

• Aortic                                                                                                 ·14
• Hearth                                                                                                 · 1
• Other                                                                                                  ·17

Rupture of aneurysm                                                                              14            (26)

• Aortic                                                                                                 · 6

Heart failure                                                                                            2              (4)

Perforation bowel                                                                                   2              (4)

Cerebral hemorrhage after balloon

 Occlusion                                                                                               2              (4)

Postangiographic bleeding                                                                       1              (2)

Gangrene after ligation of femoral artery                                                1              (2)

Cerebral infarction after carotid ligation                                                 1              (2)

Unknown (woman aged 42, necropsy refused)                                      1              (2)

Because of the vascular problems angiography was often done (51), in many patients (21) with com­plications resulting in perforation, dissection, and life-threatening bleeding, sometimes ending with femoral artery ligation or death.

OUTCOME

The mortality in the group of reported patients with vascular problems was high.  Fifty-six had died by the time of publication of the case report (50%). In most of the remaining patients the follow up time was limited, and in some it was not even indicated. The mortality among women was 54%, and among men 44%. Most patients died from bleeding complications (Table II). Two died from ischaemic complications after ligation of a major artery and two died from spontaneous perforation of the colon, again pointing to the combination of severe vascular and gastro­intestinal problems

In patients who survived there did not seem to be any reduction in thrombogenicity despite the bleeding tendency. Graftocclusions and deep vein thrombosis developed in some patients (19, 63).

SUMMARY OF SOME TYPICAL PUBLISHED CASES

1. A woman aged 37 years, (6), with no family history of EDS had skin bruising, transparent skin with cutis laxa, and hypermobile joints. Two deliveries had ended with total perineal tears. A spontaneous carotid cavernous fistula was cured by ligation of the internal carotid artery. At caesarian section there were friable tissues and heavy bleeding and difficulty with haemostasis ending up with hys­terectomy. About a year later she came to hospital with severe abdominal pain and died quickly. At necropsy a rupture of the internal iliac artery was found and the only causative factor was playing with her children.
2. A woman aged 28 years (12) who had no family history of EDS had thin skin, which bruised easily, but no joint problems. She had varicose veins, which bled repeatedly on minor trauma. At opera­tion for the varicose veins the femoral vein and deep femoral artery were torn. They were both ligated and the occluded femoral vein was bypas­sed with the saphenous vein. Two years later she developed what was considered to be a pen­tonsillar abscess, which at incision bled consider­ably. After pressure there was haemostasis but a fistula developed between the external carotid artery and the internal jugular vein. Operation disclosed a thin vein that had to be oversewn with pieces of muscle and the artery was ligated. Her immediate postoperative course was unevent­ful.
3. A boy aged 14 years (55) had hypermobile joints, cutis laxa, and tendency to bruise. His father, three brothers, and one sister had signs of EDS. Lower back pain of sudden onset was followed by collapse and the development of a large retroperitoneal haematoma that required transfusions. Aortog­raphy was attempted but it was not possible to pass the catheter. Severe