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Vascular Type

Vascular Type is generally regarded as the most serious form of EDS due to the possibility of arterial or organ rupture. The skin is usually thin and translucent with veins being seen through the skin, which is most apparent over the chest and abdomen. There are certain facial characteristics present in some affected individuals. These manifestations include large eyes, thin nose, lobeless ears, short stature and thin scalp hair. Also evident is a decrease in subcutaneous tissue, particularly in the face and extremities. 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. Acute diffuse or localized abdominal or flank pain is a common presentation of arterial or intestinal rupture. Life expectancy is shortened with a majority of individuals living only into their forties. Pregnancies may be complicated by intra-partum uterine rupture and pre- and postpartum arterial bleeding. Treatments are available which may help extend life, and surgical interventions are improving.

Joint hypermobility is usually limited to the digits. Tendon and muscle rupture can occur. Talipes equinovarus (clubfoot) is frequently seen at birth. Other manifestations that may be found in the Vascular Type include: acrogeria (premature aging of the skin of the hands and feet); early onset varicose veins; arteriovenous fistula (an opening between an artery and vein), carotid-cavernous fistula; pneumothorax (collapse of a lung) /pneumohemothorax (collapse of a lung with a collection of air or gas and blood); gingival recession and complications during and after surgery (i.e. wound dehiscence).

The Vascular Type of EDS is caused by structural defects in the proa1(III) chain of collagen type III encodes by COL3A1. This type of EDS is inherited in an autosomal dominant manner. A skin biopsy can diagnose this type of EDS.

Vascular Frequently Asked Questions

Ehlers-Danlos syndrome (EDS) is an inherited connective tissue disorder with varying manifestations that have been classified into six major types: Classical (type I & II), Hypermobility (type III), Vascular or VEDS (type IV), Kyphoscoliosis (type VI), Arthrochalasia (types VII-A & B), and Dermatosparaxis (type VII-C). EDS is caused by a defect in the formation of collagen, specifically mutations in the COL5A and COL3A genes, which can cause hypermobility in joints. EDS gets its name after two physicians who identified it at the turn of the 20th century, Edvard Ehlers (Denmark) and Henri-Alexandre Danlos (France).

The types of EDS are not gradations in severity, but represent distinct disorders that "run true" in a family. The different types are classified according to their manifestations of signs and symptoms. The underlying features of all forms of EDS is a genetic alteration at the molecular level which causes abnormalities and (weakened) defective connective tissue within the collagen itself.

Collagen is a protein that acts like "glue", which holds the body together, and makes the connective tissue strong and provides elasticity. Each type of EDS has a different collagen abnormality, but all share, in varying degrees certain manifestations. This faulty collagen causes structural changes to the skin, ligaments, tendons, bone, fascia and eyes. Some types of EDS are characterized by weaknesses in the walls of the hollow organs of the gastrointestinal tract, in the esophagus, the cardiovascular system, uterus, bladder, blood vessels and the arteries. Diagnosing a specific type of EDS may not be easy, however, because the manifestations often overlap. The fundamental understanding of this complex disorder and its varied manifestations is essential to prevent major life-threatening complications.

There are varying degrees of severity with EDS that can range from having loose joints which may dislocate easily with few other complications, to connective tissues which are so fragile — the skin splits and gaps with minimal injury, to extreme dislocations/laxity of joints which don't stay in place, to major blood vessels that may rupture and produce internal bleeding or the bowel may rupture. EDS may include:

Skin

Some patients may have fragile soft velvet-like skin, stretchy skin (hyperextensibility), very doughy skin, and/or some have thin skin which shows the underlying blood vessels. The condition of fragile skin that tears easily and that is susceptible to easy bruising can be mild to severe. Other characteristics of EDS patients’ skin includes "cigarette paper" scars, slow healing, severe scarring, slow and poor wound healing, and 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); shoulders, spine, elbows, wrists, knees, ankles, and laxity in the hands and fingers; and early onset of osteoarthritis.

Hollow Organs

Aortic root dilatation, aortic aneurysms, aortic rupture, bowel rupture and uterine fragility have all been noted in patients with EDS. These are more commonly found in the Vascular (VEDS) Type, though.

Miscellaneous/Less Common

Chronic, early onset, debilitating musculoskeletal pain (usually associated with the Hypermobility 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.

EDS is genetic. There are two different inheritance patterns of EDS. They are known as autosomal dominant and autosomal recessive. It is important to remember that regardless of the pattern of inheritance, we have no control over which genes we pass on to our children. Depending on the EDS type, there are significant percentages of affected individuals who have a de novo disease-causing mutation. What is autosomal dominant? What is autosomal recessive?

Mosaicism denotes the presence of two populations of cells in one patient, where one of the two is usually affected by a genetic disorder. Although most forms of trisomy are due to problems in meiosis and affect all cells of the zygote, there are cases where the trisomy only occurs in a selection of the cells. Generally this leads to a milder phenotype than in non-mosaic patients with the same disorder. Post-zygote event: a mutational event or abnormally in chromosome replication/segregation that occurs after fertilization of the ovum by the sperm, often leading to mosaicism. Germline mosaicism denotes two or more genetic or cytogenetic cell lines confined to the precursor (germline) cells of the egg or sperm, formally called gonadal mosaicism. Somatic mosaicism denotes two or more genetic or cytogenetic cell lines within the cell of the body (may or may not include the germline cells). Isolated: an abnormality that occurs in the absence of other systemic involvement.

Resources: Milewicz, D. M., Witz, A. M., Smith, A. C. M., Manchester, D. K., Waldstein, G., Byers, P. H.: Parental somatic and germ-line mosaicism for a multiexon deletion with unusual endpoints in a type III collagen (COL3A1) allele produces Ehlers-Danlos syndrome type IV in the heterozygous offspring. Am. J. Hum. Genet. 53: 62–70, 1993.

Genetic counselors are medical professionals who are trained in medical genetics and counseling. They deal with the occurrence or risk of occurrence of a genetic disorder in a family. They most often work in conjunction with a medical geneticist (physician). They provide an accurate presentation of the facts to a patient who has been diagnosed or who is a known carrier of a genetic disorder. Most people find the genetic aspect of the disorder confusing.

A genetic counselor will help you sift through the facts to gain a better understanding of your inheritance pattern. They provide nondirective counseling to those who are considering starting a family to facilitate making an informed decision. They may act as a resource for educational information about a disorder, as a psychosocial counselor for families in crisis, as a link to support services/support groups and as a coordinator for patient care.

Laboratory confirmation of certain types of Ehlers–Danlos syndrome is possible. These include the Classical, Vascular (VEDS), Kyphoscoliosis, Arthrochalasia and Dermatosparaxis Types. If these types of EDS are suspected based on the clinical findings, the geneticist or your physician may recommend or offer laboratory confirmation.

The genetic counselor may be the liaison between the patient and the genetic laboratory. In this role the counselor may be responsible for explaining the technical information to patients and other health care providers. The genetic counselor will most often be the person to explain how the testing will be done, the costs involved and the estimated length of time for test completion.

The tests involved are usually performed at highly specialized laboratories. Because they are often not the center where a person is being evaluated, the genetic counselor may also be responsible for gathering all pertinent medical information such as medical records, family history and consent forms. When lab results become available, the genetic counselor and the geneticist will meet with the patient or family to discuss the results and implications of the new findings.

Currently, there is no cure for Ehlers-Danlos syndrome, so medical intervention is limited to symptomatic therapy, prophylactic measures and counseling. Some individuals with EDS have little disability, whereas other people can be severely handicapped. Often, people are plagued with chronic pain. EDS must be treated on an individualized basis and discussed with your primary caretakers. EDS is generally not a disorder which causes someone to "stick out like a sore thumb." Often individuals describe a frustration at having to restrict various activities and trying to explain why to others. Many individuals learn to cope with their disorder and have the potential to pursue countless careers and lead a full and active life. However, some patients are troubled by hypotonia (low muscle tone), joint instability and chronic joint pain. These symptoms should be recognized and discussed, and lifestyles and professional choices should be adapted accordingly.

EDS is a lifelong condition, some individuals may face social obstacles related to their disorder on a daily basis. Some report living with fears of significant and painful skin ruptures, becoming pregnant (especially those with Vascular EDS), their condition worsening, unemployment, physical and mental burdens and social stigmatization's in general.

Resources: Java O. Solis, MD: A Health Advantage, "Ehlers-Danlos Syndrome"

For each individual with EDS, the clinical story is unique. There isn't a single answer as to why an individual might have features of more than one type of EDS. The first step that they could take to sort this out is to visit a medical geneticist. It is possible that they might benefit from laboratory testing to confirm the molecular or biochemical basis of the form of EDS that they have. Sometimes, but not always, the testing helps to clarify the clinical confusion. It may be, however, that they have features of more than one type of EDS because they have a connective tissue disorder that hasn't yet been "described," meaning that the underlying protein abnormality or gene mutation is unknown. Future research studies will be necessary to answer the question. Answered by Melanie Pepin MS, CGC

The "vascular events" that occur in Vascular Ehlers Danlos syndrome (VEDS) include arterial dissection, arterial rupture, arterial aneurysm and organ rupture. When these occur, the result may be an infarct (loss of blood supply), a bleed into an open space or an organ or an occlusion. In addition to these events, individuals with VEDS often, although not always, have a lifelong history of easy bruising. Any or all of these vascular problems can occur in the absence of VEDS, in a "normal" individual. When they do occur, they may occur at a later age than in VEDS, to a lesser degree or much less often. The challenge for the physician is to sort out whether the "vascular event” that the patient describes or experiences is a consequence of normal aging and living, or the consequence of an underlying collagen disorder. The same issues apply when considering vascular events in people with other forms of EDS. If a person with hypermobile EDS experiences a vascular event, the physician will need to consider whether this is coincidence or an association. The research studies that could be done to determine if individuals with other forms of EDS are at increased risk (as compared to the general population) have not been done. Answered by Melanie Pepin, MS, CGC

Bruising is common; vascular rupture, dissection, etc. are not in other forms of EDS. Answered by Peter Byers, MD

All people with EDS should have a routine physical examination that includes an assessment of blood pressure and auscultation of the heart (listening to the heart). At this point, unless there is a rhythm disturbance (irregular heart beat) or a murmur, there is no consensus in the literature what people should have further examined. This is an emerging field. Studies are now being done to assess if MRA, for example, would be helpful in imaging and following people with Vascular EDS (type IV). Some people with Classical EDS (type I) appear to have a risk for aortic enlargement, but who and what proportion are not known so further study is needed. Answered by Peter Byers, MD

A routine noninvasive cardiovascular evaluation should be performed in all EDS patients in order to exclude valvular heart disease and dilation of the aortic root or other vessels, including the coronary arteries. [DiMario et al., 1988 Jpn Heart J 29 (4): 491–6]

Due to the recent study [R. Wenstrup et al., 2002], looking at the incidence of aortic root dilation in non-Vascular Type EDS (22% in Hypermobility, 33% in Classical) Dr. Lavallee recommends ultrasound imaging the heart and aorta every two years for most patients and yearly ultrasounds for those with known dilatation, Vascular Type, hypertension, involved in a highly dynamic sport or diabetic. Answered by Mark Lavallee, MD, FACSM

Dysautonomia means dysfunction of the autonomic nervous system. The autonomic nervous system is the master regulator of all unconscious organ function throughout the body. It is involved in the control of heart rate, blood pressure, temperature, respiration, digestion and other vital functions. Dysfunction of the autonomic nervous system can produce the apparent malfunction of the organs it regulates. For this reason, dysautonomia patients often exhibit numerous, seemingly unrelated maladies.

Orthostatic intolerance is present when patients experience symptoms such as lightheadedness, palpitations and tremulousness during standing. Many patients also note other symptoms with upright posture: visual changes, discomfort in the head or neck, throbbing of the head, poor concentration, tiredness, weakness and occasionally fainting. Patients can be severely impaired by these symptoms and signs, such as a bluish-red suffusion of skin in the lower extremities on standing, which are relieved by lying down.

Postural Orthostatic Tachycardia Syndrome (POTS)

Often more simply referred to as postural tachycardia syndrome, or POTS, this disorder is characterized by the body's inability to make the necessary adjustments to counteract gravity when standing up. The defining symptom of POTS is an excessive heart rate increment upon standing. However, as you will discover, there are a multitude of other symptoms that often accompany this syndrome. POTS can be a difficult disorder to detect and understand.

More information on POTS.

Neurocardiogenic Syncope (NCS)

Sometimes referred to as neurally mediated syncope or vasovagal syncope, this disorder is characterized by an episodic fall in blood pressure and/or heart rate that results in fainting [Robertson, 2002].

Pure Autonomic Failure (PAF)

Pure Autonomic Failure is a degenerative disease of the peripheral nervous system characterized by a marked fall in blood pressure upon standing (orthostatic hypotension). The orthostatic hypotension leads to symptoms associated with cerebral hypoperfusion, such as dizziness, fainting, visual disturbances and neck pain [Mathias, Mallipeddi & Bleasdale-Barr, 1999]. Other symptoms such as chest pain, fatigue and sexual dysfunction may also occur. Symptoms are worse when standing and are sometimes relieved by sitting or lying flat.

References:

Mathias, C. J., Mallipeddi, R. and Bleasdale-Barr, K. (1999). Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy. Journal of Neurology, 246, (10), 893–898.

MEDLINEPlus Heath Information. (2003). Multiple System Atrophy. Retrieved September 8, 2003 from: http://www.nlm.nih.gov/medlineplus/ency/article/000757.htm

Extraarticular manifestations of the joint hypermobility syndrome may include the peripheral nervous system. The autonomic nervous system-related symptoms of the patients have a pathophysiological basis which suggests that dysautonomia is extraarticular manifestation in the joint hypermobility syndrome. 

Resources: [Gazit Y., Nahir AM, Grahame R, Jacob G. "Dysautonomia in joint hypermobility syndrome" Am J Med. 2003 Jul; 115 (1): 33-40. Comment in: Am J Med 2004 Jun 1; 116 (11):783; author reply 783–4.]

"Physicians propose that these syndromes occur together due to abnormal connective tissue in dependent blood vessels in those with EDS, which permits veins to distend excessively in response to ordinary hydrostatic pressure. Simply put, this connective tissue abnormally allows excessive amount of blood to pool in these patient's lower limbs when they stand."

Resource: [Rowe et al. 1999]

Sleep complaints are frequently reported by patients with Marfan and Ehlers-Danlos syndrome (EDS). We examined the exact nature of sleep complaints in these patients. Periodic limb movements were reported more often in EDS (67%, p = 0.02) than in Marfan (27%, p = 0.25) compared to controls (8%). Pain and back complaints were highly presented in both groups, but most pronounced in EDS patients. Our study calls for greater attention to the presence of apnea, pain and periodic limb movements in these patients. 

Resources:  [Verbraecken J et al. "Evaluation for sleep apnea in patients with EDS and Marfan: a questionnaire study." Clin Genet. 2001 Nov; 60 (5): 360–5.]

All patients should see a geneticist to determine the specific type of EDS that they have, but patients considering pregnancy must receive genetic counseling so that they can make informed decisions. In addition to concern about passing EDS on to a child, a woman with EDS has an increased risk of miscarriage, premature rupture of membranes, premature births, cervical incompetence and pre-mature labor. During pregnancy there is an increase in the hormone, relaxin. Relaxin causes the connective tissue to become looser, thus increasing joint laxity perinatally. This can be so severe that walking is impossible, and causes postpartum complications. Some forms of EDS can cause serious complications such as bleeding and tearing during childbirth. Those with Vascular Type also face the possibility of uterine rupture and hysterectomy.

In connection with a natural delivery, several women with EDS have experienced incontinence, weak pelvic floor, prolapse of the uterus, sprained joints of the pelvis, separation of the symphysis pubis (the joint between the two pubic bones in the frontal lower part of the pelvis) and rupture of the rectal musculature. Some doctors recommend a cesarean section so that the mother's fragile tissue and/or pelvis are not strained. In connection with the planning of a delivery the doctor and the woman should discuss advantages and disadvantages of a natural delivery compared to a cesarean section.

About 12% of neonates with the Vascular Type of EDS have clubfoot and 3% have congenital dislocation of the hips. In childhood, inguinal hernia, pneumothorax and recurrent joint dislocation or subluxation are common [Pepin et al. 1992]. Affected individuals often have a lifelong history of easy bruising.

A delay in the onset of walking is common in individuals with familial ligamentous laxities. Some of the complaints of ligamemtary laxity are hallux valgus with metatarsus primus adductus, hallux limitus, flexor stabilization-type hammertoes, plantar fascitis, hindfoot degenerative joint disease, derangement of the knee, clubbed foot, rotated hips, increased femoral anteversion, webbed toes, curled/clawtoes, in-toeing or out-toeing, and flatfeet.

Complaints of foot and leg pain and fatigue are common, especially cramping of muscles, particularly at night. Pain is a significant problem.  Atrophy caused because of low muscle tone. Protective and supportive measures such as molded ankle foot orthoses many be necessary to support the child with ligamentous laxity for ambulation and to prevent injuries. Agnew P. "Evaluation if the child with ligamentous laxity.

Resource:  " Clin Podiatr Med Surg 1997 14 (1): 117–30.]

There are no studies to refer to about what effects nutrition, vitamins and herbal supplements have on the EDS patient. However, many EDS patients have had some benefits from certain diets, vitamins (especially vitamin C), zinc, magnesium, glucosamine, chondroitin, etc. This is an individual choice. Before starting any new treatment or supplements, always seek a consultation and advice from your medical doctors concerning the effects of these supplements. There may be interactions to be aware of.

Intracellular erythrocyte magnesium (RBC Mg) for muscle cramps and migraines were more frequent in Mg-deficient patients. Low potassium is likely to cause muscle weakness and even paralysis.

Resources: [Coghlan HC, Natello G. "Erythrocyte magnesium in symptomatic patients with primary mitral valve prolapse: relationship to symptoms, mitral leaflet thickness, joint hypermobility and autonomic regulation." Magnes Trace Elem. 1991–92;10(2-4):205–14.]

Chronic recurrent headaches may constitute the neurologic presentation of EDS in the absence of structural, congenital or acquired CNS lesions that correlate with their symptoms. Individuals with EDS may be prone to migraine due to an inherent disorder of cerebrovascular reactivity or cortical excitability. Additional studies are needed to elucidate the pathogenesis of headaches in EDS. 

Resource:  [De Jacome. "Headache in EDS." Cephalalgia 1999 Nov; 19 (9): 791.]

There are many Chiari patients who also have EDS. An added caution is needed due to the diagnosis of EDS. Chiari is typically treated in one of two ways: drug management and/or surgery. With EDS, the surgical protocol must be altered to protect connective tissue, deal with arachnoid scarring or adhesions and prevent cranial-cervical instability. The surgical techniques are different, too. They are designed to protect fragile tissues and prevent or minimize bleeding, and post operatively, there is more emphasis on preventing or fixing would dehiscence. Seek out and consult with Chiari-experts before undergoing any treatment or surgery. It is generally not an emergency, unless you have any of the three red flag symptoms: choking, breathing problems or drop attacks. Those indicate more severe brainstem involvement, so don't delay in seeking treatment for them. Resource(Grubb 2002 - Rowe er.al 1999)

Hereditary disorders of connective tissue may present with Chiari I malformation, occipitoatlantoaxial hypermobility and functional cranial settling. C. Francomano, T. Milhorat, P. Bolognese, M. Nishikawa, N. McDonnell. We report an association of hereditary disorders of connective tissue (HDCT) and Chiari malformation 1 (CM1), presenting with lower brain stem symptoms attributable to occipito-atlantoaxial hypermobility and functional cranial settling. The prevalence of hereditary disorders of connective tissue (HDCT) was determined in a prospectively collected cohort of 2,813 patients with CM1. The diagnosis of Ehlers-Danlos syndrome (EDS) or other HDCT was made in 357 of 2,813 of patients with CM1 (12.7%). The clinical features of HDCT/CM1 were distinguished from those of CM1 alone by clinical stigmata of HDCT, a greater female preponderance (7:1 vs. 3:1),  a greater incidence of lower brain stem symptoms (0.43 vs. 0.05), retroodontoid pannus formation (0.71 vs. 0.16) and hypoplasia of the oropharynx (0.45 vs. 0.02). In patients with HDCT/CM1, upon sitting or standing there was reduction of the basal-dens interval (3.6 mm), enlargement of the basal-atlas interval (3.0 mm) reduction of the clivus-axis angle(10.8o), reduction of clivus-atlas angle (5.8o) and reduction of the atlas-axial angle (5.3o). These changes were reducible by cervical traction or returning to the supine position. In normal controls and patients with CM1 alone, these measurements did not change with position. The identification of HDCT in 12.7% of patients with CM1 establishes an association between these previously unrelated disorders. Patients with HDCT and symptoms suggestive of CM1 should be evaluated with brain MRIs in the supine and upright positions. Full paper available from http://bit.ly/xesPlJ.

Splice site mutations in the COL1A2 gene of type I collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or complete skipping of exon 6, as well as to mild, moderate or lethal forms of osteogenesis imperfecta as a consequence of skipping of other exons. We identified three unrelated individuals with a rare recessively inherited form of EDS (characterized by joint hypermobility, skin hyperextensibility and cardiac valvular defects). In two of them, COL1A2 messenger RNA (mRNA) instability results from compound heterozygosity for splice site mutations in the COL1A2 gene, and, in the third, it results from homozygosity for a nonsense codon. The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon and extremely unstable mRNA. In the wild-type allele, the two introns (IVS11 and IVS24) in which these mutations occurred were usually spliced slowly in relation to their respective immediate upstream introns. In the mutant alleles, the upstream intron was removed, so that exon skipping could not occur. In the context of the mutation in IVS24, computer-generated folding of a short stretch of mRNA surrounding the mutation site demonstrated realignment of the relationships between the donor and acceptor sites that could facilitate use of a cryptic donor site. These findings suggest that the order of intron removal is an important variable in prediction of mutation outcome at splice sites and that folding of the nascent mRNA could be one element that contributes to determination of order of splicing. The complete absence of pro alpha 2(I)chains has the surprising effect of producing cardiac valvular disease without bone involvement.

Resources[Schwarze U et al. "Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway." Am J Hum Genet. 2004 May;74(5):917–30. Epub 2004 Apr 09.]

Subcutaneous bleeding is caused by collagen abnormalities in the vessel wall. The high frequency of a bleeding tendency in Ehlers-Danlos patients with normal tests for haemostasis (83%) supports the conventional explanation for this clinical feature. It shows that the defects in the structural integrity of skin and blood vessels lead to easy bruising.

Resources[Anstey A, Mayne K, Winter M, Van de Pette J, Pope FM. "Platelet and coagulation studies in Ehlers-Danlos syndrome." Br J Dermatol. 1991 Aug;125(2):155­63). Disorders of Vascular Fragility, Reed E. Pyeritz MD, PhD Vol 29; (6): 2001.]

Pepin M, Schwarze U, Superti-Furga A, Byers PH. “Clinical and genetic features of Ehlers-Danlos syndrome type IV, the Vascular Type.” N Engl J Med. 2000 Mar; 342(10):673–80. Erratum in: N Engl J Med 2001 Feb 1;344(5):392.

Structural abnormalities of the gastrointestinal tract are common in EDS due to the fragility and extensibility of the tissue. Hiatal hernia, gastric, duodenal and colonic diverticula may occur. Other features which have been demonstrated are visceroptosis (protrusion of the contents of the abdomen), slow motility, delayed gastric emptying, gastric atony (lack of contraction of the stomach), recurrent abdominal pain, gastroesophageal reflux disease (GERD), megaoesophagus, irritable bowel, constipation, diarrhea, megacolon, bleeding, ruptures and perforations.

Resources: Solomon JA et al. "GI Manifestations of EDS." Am J Gastroenterol 1996 Nov; 91 (11): 2282–8. Available from http://bit.ly/UzmCCX.

Poken-Harris et al. "The Prevalence of Non-Surgical Complications in the EDS."

Primary muscular hypotonia may occur and may cause delayed motor development, problems with ambulation and mild motor disturbance. Fatigue and muscle cramps are relatively frequent. Physical therapy can teach certain exercise techniques that can strengthen muscles around joints and may help to prevent or limit damage. Hydrotherapy (taking place in water) may be less damaging to joints.

Hearing impairment and/or sensitivity can occur due to the possibility of hypermobility of the joints between these bones of the middle ear (malleus, incus  and stapes) can create problems with effective sound conduction across the middle ear. This loss of energy in route to the inner ear leads to a mild to moderate conductive hearing loss. Because the inner ear is also responsible for balance, improper function leaves some affected with bouts of dizziness. 

Resource[Amanda Jenner, Lynne Shields, PhD. "EDS Speech and Language Issues."]

The safe and effective way of treating the mild to moderate hearing impairment which can occur in EDS is with hearing aid and necessary additional aids. There is a much more common inherited disorder of hearing know as oloscterosis which can be easily confused with the type of hearing impairment that is seen in EDS. It is vitally important for the ear surgeon to be able to differentiate between the two. As the hearing loss in both is due to abnormality of the sound conduction across the middle ear. The standard treatment for oloscterosis is an operation called, a "stapedectomy". However, do not attempt to undertake a stapedectomy on an EDS patient as it could easily end in disaster with total loss of hearing and a severe disruption of balance.

Resource[M. Hawthorne, FRCS. "Hearing Impairment and EDS."]

"Estimates of the prevalence of the Vascular Type of EDS vary from 1:50,000 to 1:100,000. Because many families with the Vascular Type of EDS are identified only after a severe complication or death, it is likely that individuals/families with COL3A1 mutations with mild phenotype do not come to medical attention and therefore go undetected."

Resource[Byers et al. 1995]

This condition is inherited in an autosomal dominant pattern, which means only one copy of the altered gene is necessary to cause the disorder. About half of all cases are inherited from a parent who has the condition. The other half of cases occur in people whose families have no history of the disorder. These sporadic cases are caused by new mutations in one copy of the COL3A1 gene. It is important to note that parental somatic mosaicism for COL3A1 mutations has been documented in several families in which two affected individuals have been born to unaffected parents. [Kontusarri et al. 1992]

“However, there was a statement that said, ‘even though we did not see altered mobility in the proteins, we cannot exclude mutations in the genes.’”

This statement in our result letter refers to testing for type V collagen alterations in people who have Classical EDS (EDS type I/II). People with EDS type I/II often bruise easily, as do people with some forms of Hypermobile EDS (type III), Kyphoscoliosis EDS (type VI) and EDS type VIII. We are less sure about people with EDS type VII. Some people with an OI/EDS overlap picture have hypermobility in addition to bone fragility and may bruise easily. There are two issues about testing for Vascular EDS (type IV). First, does the testing that we do identify all individuals with the condition? Second, are there mutations in other genes that give rise to the same phenotype or a phenotype sufficiently similar to Vascular EDS (type IV) that it would be considered in the same group. We do not know the answer to the first question. We know that there are some people who have multiple vascular abnormalities, including localized aneurysms, in whom we have not identified abnormalities in type III collagen genes. We know that some of these people may have "familial aneurysm" types of disorders and there are several genes that have been "located" but not identified that could give rise to these clinical pictures. There is an occasional person who the clinician thinks has Vascular EDS (type IV) but in whom we do not find an abnormality. However, many of these come from people who do not have much clinical experience with the disorder so their judgment is to evaluate. We do know that there are certain classes of mutation in the COL3A1 gene that we find less frequently than we expect. We do not know if individuals with those mutations have a Vascular EDS (type IV) clinical picture or have something else. Is it that our tests miss these people? At this point we do not think so and, instead, we think that they may have other, perhaps related, clinical pictures. The reason that we think we find abnormalities in most people is that we not only screen at the protein level but, if there is any question, we screen at the gene level too. Answered by Peter Byers, MD

This statement, "even though we did not see altered mobility in the proteins, we cannot exclude mutations in the genes" is extracted from our "normal" result letter. Because we do diagnostic testing for Vascular EDS (type IV) by examining the protein (type III collagen), it is possible that there are individuals who have COL3A1 gene mutations that we do not detect because the gene mutation is one that doesn't "translate" into a protein abnormality – meaning it doesn't reduce the amount of type III collagen, it does not change the size of the molecule, etc. From reviewing clinical histories on patients who have had normal collagen screening studies, we think the likelihood that someone has Vascular EDS (type IV) but we miss it by doing collagen screening is small (2-3%). In instances where the clinical history is consistent with the Vascular EDS diagnosis, we sometimes do additional COL3A1 gene studies. The decision to do the additional studies is determined by the lab director (Peter Byers) and the patient's doctor after review of their history. Answered by Melanie Pepin MS, CGC

Collagen screening studies are undertaken as a means of identifying the protein (in this case, collagen) abnormality typically seen in cells from an individual with the Vascular Type of Ehlers-Danlos syndrome. If the type III collagen in the cells from the patient studied is identical to the collagen pattern of the control (normal) sample, the result is reported out as "no abnormality detected." This negative result is often described in detail in the result letter, including the fact that there may be rare instances when the collagen screening study does not detect or confirm the clinical diagnosis. The sensitivity of the collagen screening test is not 100% — it is closer to 98%. If the physician still suspects that the patient has vascular EDS, additional DNA-based testing can be considered on a case-by-case basis. Answered by Melanie Pepin, MS, CGC

Beta blockers are used to slow heart rate, slow the rate of ejection (the shear force) from the heart and reduce blood pressure. They are used routinely to lower blood pressure in people who have had aortic dissections. At the moment, some physicians are using them in people with Vascular EDS to try to reduce the risk of aortic and other arterial abnormalities. Whether it is either rational or effective we do not know. It may be too difficult to do a clinical trial given the relatively small number of affected individuals available. An effort should be made to coordinate data collection.

Celiprolol is a beta blocker that in preliminary research significantly reduced arterial dissections and ruptures, postulated to be as much as a 60% reduction (possibly through strengthening the transforming growth factor beta pathway), although there were some problems with the study. Celiprolol is not available in the US yet. For more, read “Hope for VEDS Treatment?” starting on page 16 of the Spring 2011 issue of Loose Connections, available free from the EDNF.

Ong et al.: “Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial,” The Lancet 376:1476–84, 2010.

Brooke BS: “Celiprolol therapy for vascular Ehlers-Danlos syndrome,” The Lancet 376:1443-44, 2010.

EDNF’s Clinical Reference Manual: Vascular Type available free here.

Start with a complete physical examination and family history evaluation. Testing in the laboratory then depends on the availability of protein or gene based tests and the confidence with which the examiner can come to a clinical diagnosis. We suggest that if Vascular EDS (type IV) is a question that the diagnosis be confirmed with testing. Answered by Peter Byers, MD

Yes, it does. People with Vascular EDS are more likely to have little bubbles, called bullae, in the lung tissue, and to having spontaneous pneumothorax, a condition in which air escapes from these bubbles or bullae into the space around the lung and then collapse the lung. Answered by Peter Byers, MD and Melanie Pepin, MS, CGC

In some people joint laxity can get worse with age. In others it does not. The risk of complications increases with increasing age with people with Vascular EDS (type IV). We are less sure about the natural history in other disorders. Answered by Peter Byers

There is no known medical treatment to increase the production of type III collagen. However, ascorbic acid (1 to 2 grams per day) may increase the synthesis of collagen and therefore provide slightly more of the normal type III collagen.

This is a question that is begging for an answer. The biggest question that arises is: if something is found, does that mean that it would or should be repaired? Given the delicacy of blood vessels in people with the vascular form of EDS, the answer to this is, we do not know. Would it help in predicting places most likely to be the source of trouble if you have a sudden event? Again, it is not currently known if ruptures occur at known aneurysm sites or in other areas. These are questions that need to be answered by detailed studies of people with vascular EDS. Answered by Peter Byers, MD and Melanie Pepin, MS, CGC

Most drugs, including aspirin, can be used with the approval of a physician. Drugs that induce hypertension are not a good idea. Aspirin can be used when blood vessels are narrowed by a dissection, particularly in vessels that feed the brain, to maintain flow. So there is never a never with medications and it is always a matter of appropriate care. Answered by Peter Byers, MD and Melanie Pepin, MS, CGC

With respect to inadvertently elevating blood pressure, patients/physicians should be mindful of the impact that certain kinds of drugs may have on those with EDS, especially those with the Vascular EDS. The possibility exists that the Vascular patient may have undiagnosed aneurysms.

"Over-the-counter" medications that include decongestants can drive your blood pressure up. These are used in cold/sinus/cough preparations. Pure "antihistamines" without are generally safe, as are several prescription preparations. Control of high blood pressure may help prevent some aneurysms. Control of all risk factors associated with atherosclerotic disease (diet, exercise, cholesterol control) may help prevent aneurysms or their complications. [Medline Plus Medical Encyclopedia entry on Aneurysm]

Vascular EDS is a very rare cause of aortic dissection and many other conditions, including Marfan syndrome and familial aortic aneurysm are more common. The most common predisposing factors for aneurysm and dissection are hypertension and atherosclerosis. Answered by Peter Byers, MD and Melanie Pepin, MS, CGC

In childhood many individuals with Vascular EDS are first thought to have a coagulation disorder. Bleeding disorders can arise from disorders of the vessel wall defects, platelets and coagulation. There are some patients with EDS, however, who have been diagnosed with Von Willebrand, Factor deficiencies and even Haemophilia. Most laboratory studies reveal bleeding and clotting times to be normal, even though most require blood transfusions and intravenous alimentation. Recent studies have shown that the increased bleeding tendency probably is due to a defect in the collagen structure of the vascular and perivascular tissues. Possible capillary fragility and venous varicosities may also occur. There is also a reduction in the ability of abnormal collagen in patients with EDS to attract platelets, which may contribute to the bleeding tendency. [Karaca et al. "Abnormal platelet collagen reaction in EDS" J Haematol 1972; 9:465–9. Wesley TA. "Multiple surgical problems in two patients with EDS" Surgery 1980;87 (3): 319–24]

“The diagnosis of EDS type IV is based on clinical findings and confirmed by identification of a causative mutation in COL3A1, the only gene in which mutations are known to cause EDS type IV. Sequence analysis detects 98% of mutations, while rare exonic deletions are detected by COL3A1 deletion/duplication analysis or collagen screening and cDNA amplification. Analysis of collagens produced by cultured fibroblasts ("biochemical studies") from affected individuals can demonstrate abnormalities of type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility in cells from some individuals in which no mutation was detected by genomic sequencing.”

Resource[Melanie G Pepin, MS, CGC and Peter H Byers, MD. Ehlers-Danlos Syndrome Type IV. GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1494/.]

Clinicians and physicians should take this into consideration. It is recommended that a routine noninvasive cardiovascular evaluation should be performed in all patients with EDS in order to exclude valvular heart disease and dilation of the aortic root or of other vessels, including the coronary arteries. [Di Mario et al. 1998 Jpn Heart J 29 (4): 491–6]

In Vascular EDS patients, an abnormally low intima-media thickness generates a higher wall stress than in control subjects at the site if an elastic artery, which may increase the risk if arterial dissection and rupture. [Boutouyrie et al. "Increase Carotid all Stress in Vascular EDS." Circulation 2004; 109: 1530–1535]

Carotid arteries, but not aorta and radial artery, displayed abnormal elastic properties in spontaneous cervical artery dissection patients. Higher stiffness of carotid wall material and circumferential wall stress could increase the risk of dissection in these patients. [Calvet D. et al. Stroke 2004; 35: 2078]

In Autosomal Dominant inheritance, only one gene from the parent needs to be functioning improperly for an individual to be affected. When an affected person has children, there is a 50% chance with each pregnancy that the parent will pass on the changed gene to his/her children. Therefore there is a 50–50 chance that the child will be affected, regardless of the sex of the child. A person who does not carry the changed gene is not affected and cannot pass the gene on to his/her children. EDS types that are inherited in the autosomal dominant fashion include the Classical Type , Hypermobility Type, Vascular (VEDS) Type and Arthrochalasia Type. Most cases of EDS seem to follow the autosomal dominant pattern of inheritance.

More Information about Autosomal Dominant at medterms.com.

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