Are You Confident of the Diagnosis?
The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility affecting skin, ligaments, joints, blood vessels, and internal organs. As a group, the Ehlers-Danlos syndromes are clinically and genetically heterogeneous and have a combined prevalence estimated at 1:10,000 to 1:25,000. The revised Villefranche nosology categorizes six clinical types of EDS.
Classical EDS is characterized by marked skin hyperextensibility, widened atrophic scars, easy excessive bruising and joint hypermobility. The major diagnostic criteria for the hypermobile type of EDS include moderate skin hyperextensibility and/or smooth, velvety skin, easy bruising and moderate-to-marked generalized joint hyperextensibility.
In vascular EDS, the hallmark features are thin, translucent skin, lack of subcutaneous fat, extensive bruising, characteristic facies (gaunt, prominent eyes, thin nose, and small mouth), short stature, and arterial, intestinal and uterine fragility or rupture. In the kyphoscoliotic forms there is severe muscle hypotonia and scoliosis at birth, scleral fragility and rupture of the ocular globe, as well as generalized joint laxity.
The arthrochalasia type is characterized by severe generalized joint laxity with recurrent subluxations and congenital bilateral hip dislocation. In the dermatosparaxis type, the major features are severe skin fragility as well as sagging, redundant skin.
The classical, hypermobile, and vascular types compose the majority of cases of EDS; the hypermobile (by far the most common) and classical forms are more common than the vascular form. The other types of EDS are much less common, of which little is known about the pathophysiology and genetic defect in some of the subtypes (Table I).
|Classical♦||AD||Type V procollagen||COL5A1, COL5A2, COL1A1*|
|Hypermobile♦||AD||Unknown mainly, rarely tenascin X or procollagen III||TNXB*, COL3A1*|
|Vascular♦||AD||Type III procollagen||COL3A1|
|Kyphoscoliotic♦||AR||Lysyl hydroxylase deficiency||PLOD1|
|Arthrochalasia♦||AD||Deletion of N-proteinase cleavage site in type I procollagen||COL1A1, COL1A2|
|Dermatosparaxis♦||AR||Procollagen N-peptidase deficiency||ADAMTS2|
|Cardiac valvular||AR||Type I procollagen||COL1A2|
AD, autosomal dominant; AR, autosomal recessive; XL, X-linked.
*Rare or limited patients identified with specific genetic alteration.
♦Denotes the six clinical types categorized by the revised Villefranche nosology.
The classical form of Ehlers-Danlos syndrome (formerly called EDS type I and II) is characterized by marked skin hyperextensibility, easy bruising, widened atrophic scars and joint hypermobility. There is considerable overlap between the classical and hypermobile types of EDS.
What you should be alert for in the history
Patients with classical EDS have large and small joint hypermobility that often predispose to joint subluxation and dislocation even with little or no trauma. Constant or chronic pain and fatigue are common and can be a particularly psychosocially debilitating aspect of the condition. There may be delayed gross motor development because of joint hypermobility.
At least 50% of patients with the classical and hypermobile types of EDS experience functional bowel disorders, such as functional constipation or diarrhea. Patients with the classical and hypermobile types of EDS may have features of autonomic dysfunction including postural orthostatic tachycardia syndrome (POTS); one third to one half report atypical chest pain, palpitations, and/or dizziness when changing positions rapidly.
Cardiovascular involvement in these patients is similar in the classical and hypermobile types. Aortic root dilatation may occur but is generally to a mild degree. Previously aortic involvement has been reported in about one third of these patients, although not usually in children. Use of modern diagnostic criteria for mitral valve prolapse (MVP) has shown that MVP is not more prevalent in EDS than in the general population. In our experience, MVP and aortic dilation are rare in children.
Poor wound healing after trauma or surgical intervention is common and a manifestation of tissue fragility. Scars tend to be wide, atrophic, and “cigarette-paper”-like (Figure 1). Easy bruising frequently occurs, often with residual characteristic brownish discoloration as a result of frequent recurrences in the same area, commonly on the shins and knees (Figure 2, Figure 3).
Hematologic complications such as easy bruising, prolonged bleeding, menometrorrhagia (excessive frequent uterine bleeding), and epistaxis occur and are due to capillary fragility. There are normal bleeding times, von Willebrand factor, platelet number and function, and coagulation studies.
Premature rupture of membranes, prematurity, and /or breech presentation are more common in the in utero histories of patients with classical EDS than in the general population. In affected women, tearing of the perineal skin by forceps, extension of the episiotomy incisions, postpartum hemorrhage and prolapse of the uterus and or bladder may occur.
Characteristic findings on physical examination
Joint hypermobility is generalized, affecting small and large joints. Measurement of hypermobility can be based on the Beighton scale (Table II), which is the most widely accepted grading system for joint hypermobility and allows for an objective semi-quantification of joint hypermobility. A score of 5/9 or greater defines hypermobility. Skin hyperextensibility should be tested at a site that is not easily stretched, such as the dorsal surface of the hand, forearm, and neck; it is characterized by skin that easily extends away from the surface when pulled, and then coils back after released.
|Hypermobility Test||Scoring – Points|
|Passive dorsiflexion of the little fingers beyong 90 °||One point for each hand|
|Passive appositition of the thumbs to the flexor aspect of the forearm||One point for each hand|
|Hyperextension of the elbow beyond 10 °||One point for each elbow|
|Hyperextension of the knees beyond 10 °||One point for each knee|
|Forward flexion of the trunk with knees fully extended so that the palms of the hands rest flat on the floor||One point|
The common areas of atrophic wide scars are forehead, chin, and legs. Less frequently there is acrocyanosis, subcutaneous spheroids (particularly over the shins), molluscoid pseudotumors, piezogenic papules, elastosis perforans serpiginosa, and chilblains. Occasionally, sclera may be blue/grey.
Expected results of diagnostic studies
Generally, the diagnosis of classical EDS is established on the basis of clinical examination and family history. Approximately 50% of people with classical EDS will have mutations in either COL5A1 or COL5A2 genes. Gene studies are not generally useful if a clinical diagnosis has been made but could be done for prenatal counseling.
There is considerable overlap between the classical and hypermobile forms. The hypermobile form of EDS is most common and thought to be the most benign. Patients with hypermobile EDS have joint hypermobility of small and large joints, which is the primary manifestation. They may have soft, doughy skin, mild increased extensibility of the skin, and easy bruising. However, the main distinguishing phenotype is that they do not have atrophic scarring, which is one of the three major criteria in classical EDS.
Similar to hypermobile EDS is tenascin X deficiency, caused by homozygous mutations in the TNXB gene; this is thought of as an autosomal recessive form of EDS. These patients have mild joint hypermobility, skin hyperextensibility, and easy bruising. The defining feature that is lacking in this diagnosis and present in classical EDS is atrophic scarring.
In patients with familial joint hypermobility syndrome the only clinical feature is joint hypermobility. These patients do not have the dermatologic findings observed in classical EDS, but it is possible that they have a milder form of hypermobile EDS.
Intentional (non-accidental) trauma may be diagnosed, incorrectly, in a child with multiple recurrent bruises.
What you should be alert for in the history
Hypermobile EDS is generally thought to be the most common and the most benign of the Ehlers-Danlos syndromes; however, significant complications can occur and primarily involve the musculoskeletal system. Frequent joint subluxation and dislocation after limited or no trauma may occur. Chronic pain in this condition can be both physically and psychologically debilitating, affecting people of all ages. Pain was found to be more common among patients with the hypermobile form of EDS than the classical and vascular forms in a recent study.
The skin involvement in these patients is often minimal; however, it can be soft/doughy with mild-to-moderate hyperextensibility and easy bruising. Hematologic concerns similar to those in the classical form occur although less frequently: prolonged bleeding, menometrorrhagia (excessive frequent uterine bleeding), and epistaxis. In many patients prior to establishment of the correct connective tissue diagnosis, other diagnoses such as chronic fatigue syndrome, fibromyalgia, depression, and hypochondriasis are made. Psychological dysfunction including depression, anxiety and low self-esteem are more common in this group of patients than in controls.
Similar to patients with classical EDS, there may be a history of premature rupture of membranes and rapid labor and delivery in people with hypermobile EDS, however, less frequently than in the classical form.
Characteristic findings on physical examination
Characteristic findings on physical examination are based on the major diagnostic criteria for this condition, which include joint hypermobility and skin hyperextensibility; hypermobility is generalized in large and small joints of limbs, temporo-mandibular joints and vertebral column. Flat, pronated feet occur commonly and cause pain in different areas of the lower limbs (Figure 4). The skin may be hyperextensible, feel smooth and velvety, and have multiple bruises. Occasionally, sclera may be blue/grey.
Expected results of diagnostic studies
The biochemical cause of hypermobile EDS is unknown in most cases. Haploinsufficiency of tenascin X has been associated with a small portion of patients with the clinical diagnosis of EDS hypermobility type. Tenascin X is encoded by the TNXB gene. In cohorts of patients in which TNXB mutations were identified, the phenotype consisted primarly of joint laxity and soft skin; however, the patients did not have easy bruising or increased skin extensibility.
There is considerable overlap between the hypermobile and classical types of EDS, with the main differentiating feature being absence of tissue fragility evidenced by lack of atrophic scarring in hypermobile patients. In familial joint hypermobility syndrome the only clinical feature is that of joint hypermobility. These patients do not have the dermatologic findings observed in hypermobile EDS.
There are many other heritable disorders of connective tissue that manifest with some degree of joint hypermobility, including Marfan syndrome, Loeys-Dietz syndrome, and osteogenesis imperfecta. In these other connective tissue disorders there are additional clinical findings that are not observed in patients with hypermobile type EDS.
In the less severe, non-lethal forms of osteogenesis imperfecta caused by defects in type I collagen (COL1A1 and COL1A2) there is joint laxity, easy bruising, frequent fractures, occasional blue-grey sclera, dentinogenesis imperfecta, and premature hearing loss.
Marfan syndrome is characterized by skeletal involvement (including very tall stature) arachnodactyly (disproportionately long fingers and toes), dolichostenomelia (disproportionately long limbs), scoliosis, anterior chest deformity, typical facial features (including long thin face, deep-set down-slanting palpebral fissures, high narrow palate, horizontal chin crease and high nose bridge), striae on the back (horizontal), shoulders, thighs or knees, high myopia and/or lens dislocations, MVP, progressive aortic aneurysm and dissection. Marfan syndrome is caused by mutations in the gene FBN1.
Loeys-Dietz syndrome is characterized by craniofacial abnormalities (widespaced eyes, bifid/notched/wide/short uvula), skeletal differences (including scoliosis and pectus abnormality) and aneurysms, arterial dissections, and vessel tortuosity caused by mutations in the TGFβR1 and TGFβR2 genes.
What you should be alert for in the history
Vascular EDS is characterized by thin translucent skin with visible veins, arterial, intestinal and uterine fragility or rupture, extensive bruising, and a characteristic facial appearance (gaunt, prominent eyes, thin nose, and small mouth). Patients may be short and have a wasted appearance due to lack of subcutaneous fat. There may be a family history of sudden death. Joint hypermobility and skin hyperextensibility are not prominent in the vascular form of EDS.
Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (50%), head and neck (25%), and extremities (25%). Occasionally there may be subdural or intracerebral bleeds after trauma.
The average age of the first major arterial or gastrointestinal complication is 23 years. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with vascular EDS. The majority of gastrointestinal perforations occur in the sigmoid colon, rarely occurring in the small bowel or stomach. Gastrointestinal rupture is rarely a cause of death in these patients, and surgical intervention for the bowel rupture is necessary and generally lifesaving. The mean age of death is approximately 48 years.
Pregnancy carries a high risk of maternal death owing to uterine rupture.
In neonates there may be a history of club foot (about 13%) and congenital dislocation of the hip (3%). In children, inguinal herina, pneumothorax, and joint dislocations or subluxations may occur. However, many children without a family history might have been investigated for “failure to thrive” because of lack of subcutaneous fat and short stature but go undiagnosed until they manifest their first major complication.
Characteristic findings on physical examination
Short stature; lack of subcutaneous fat; the facial appearance may be subtle or extreme with large, “proptotic” eyes due to lack of subcutaneous fat, thin nose, thin lips and philtrum, and small chin. Patients with vascular EDS have extremely easy bruising and thin translucent skin with easily seen veins, most notably on the chest and abdomen. They may have an acrogeroid appearance of their extremities, particularly their hands.
Unlike the classical and hypermobile forms of EDS, joint hypermobilty is not marked in the vascular form of EDS and skin is not hyperextensible. The small joints are mainly involved, but large joints may be hypermobile as well.
Expected results of diagnostic studies
The vascular form of EDS is caused by mutations in the gene COL3A1, which encodes type III procollagen molecules. Confirmation of the diagnosis is very important becuase of natural history and prognosis. It is based on synthesis of abnormal type III procollagen molecules in cultured fibroblasts or through identification of a causative mutation in COL3A1. The majority of identified mutations result in the substitution of another amino acid for glycine residues in the Gly-X-Y 343 triplets of the triple helical domain. Other mutations affect splice sites and induce exon skipping.
Loeys-Dietz syndrome, caused by mutations in the TGFβR1 and TGFβR2 genes, is characterized by many of the similar features to vascular EDS such as arterial dissections, aneurysms and vessel tortuosity, thin skin with easily visible veins, and occasional hollow organ rupture. It is differentiated by more prominent joint hypermobility, craniofacial abnormalities (bifid/short/wide uvula or cleft palate, hypertelorism) and skeletal deformities including scoliosis and pectus excavatum/carinatum. However, some patients originally thought to have vascular EDS have been shown to have Loeys-Dietz syndrome with molecular studies.
In patients with the overlapping features observed in vascular EDS and Loeys-Dietz syndromes, molecular testing is particularly important to ensure the correct diagnosis. There are significant differences in these conditions regarding patient management and prognosis.
Intentional (non-accidental) trauma may be diagnosed, incorrectly, in rare instances of a child with vascular EDS who has subdural or intracerebral bleeds after accidental trauma and also has bruises.
In the kyphoscoliotic form of EDS, tissue fragility and vascular rupture are overlapping features with the vascular type; however, the kyphoscoliotic type also includes progressive scoliosis, hypotonia, and fragility of the globe. The kyphoscoliotic form is an autosomal recessive form of EDS and is caused by mutations in the PLOD1 gene.
The periodontal form of EDS is a rare connective tissue condition with features of both classical and vascular EDS. However, in this type there is early periodontal friability, which is not observed in the other forms.
Marfan syndrome is characterized by aortic aneurysm and dissection and is caused by mutations in the gene FBN1. Patients with Marfan syndrome also have striae, skeletal involvement (including tall stature, arachnodactyly, dolichostenomelia, scoliosis, anterior chest deformity), and typical facial features (including deep-set down-slanting palpebral fissures, long thin face, with horizontal chin crease and high nose bridge) that do not resemble the face in vascular EDS. Intestinal and uterine fragility or rupture do not occur.
Who is at Risk for Developing this Disease?
EDS is a group of inherited disorders with hypermobile joints and skin changes; each subtype has a different cause. EDS is a Mendelian inherited disorder and the majority of EDS subtypes, in which the cause is known, are inherited in an autosomal dominant pattern. A complete family history is important to clarify the type of EDS and identify other at-risk family members, although a negative family history does not rule out a diagnosis of EDS.
EDS is a relatively common disorder. The classical form of EDS has an approximate incidence of 1:20,000 with the hypermobility type of EDS, which appears to be the most common form, having an approximate incidence of 1:5,000 to 1:20,000 live births.
Establishing the diagnosis, and therefore the population incidence, of EDS is difficult. The mild forms of the disorder may be under-recognized as many family members with EDS may be identified only after a single proband comes to medical attention. There is also significant clinical overlap between the hypermobility type of EDS and the joint hypermobility syndrome, which may lead to difficulty in establishing a diagnosis; in our opinions, this is not crucial because similar management may be recommended.
In EDS there is no racial, ethnic predisposition or identifiable risk factors. There should be no significant gender differences among those presenting for care, but females are more likely to be identified. Gender bias for the diagnosis of EDS is not well understood and cannot be attributed to social or genetic factors alone.
EDS can be inherited in various Mendelian patterns (AD, autosomal recessive, and X-linked inheritance). In some people, it may be the result of a new mutation (Table I) but is heritable, so that it can be passed on to that person’s children. The most common forms of EDS, the classical, hypermobile and vascular forms, are inherited in an AD pattern although only 50% of individuals diagnosed with EDS have an affected biological parent.
A complete family history (pedigree) should be obtained when considering a diagnosis of EDS; different family members may be reported to have only some features including chronic fatigue, chronic pain, or fibromyalgia. A negative family history does not preclude the diagnosis, if there is a de novo (new) mutation or AR inheritance.
What is the Cause of the Disease?
In the subtypes of Ehlers-Danlos syndrome (EDS) in which the specific etiology is known, EDS results from defective collagen biosynthesis, which normally involves many mechanisms. The genetic alterations affect the production or modification of collagen. It results in abnormal assembly, modification, secretion, fibrillogenesis and/or interatction of collagen with other components within the extracellular matrix (Table I).
In general, disorders involving the structural collagen genes are the result of autosomal dominant (heterozygous state) mutations. Disorders resulting from enzymes that modify collagen are inherited in an autosomal recessive (homozygous or compound heterozygous state) pattern. A trait that is inherited in a dominant pattern, whether involving autosomal or sex chromosome, infers that a mutation on a single allele will result in the disease state despite the presence of a wild type (normal) allele on the other chromosome. A recessive disorder occurs when there is an abnormal gene on each allele (both paternal and maternal chromosomes). The most common forms of EDS are inherited in an AD pattern.
In approximately 50% of individuals with the clinical diagnosis of classical EDS a mutation in either COL5A1 or COL5A2 is identified; a small percentage with classical EDS has a mutation in COL1A1. In the majority of patients with an identifiable mutation, the phenotype of classical EDS has been associated with half the expected amount of collagen type V (haploinsufficiency). Incorporation of an abnormal collagen type V (dominant-negative effect) has also been associated with the disease phenotype. There appears to be no phenotypic distinction between those patients with classical EDS found to have haploinsufficiency of collagen type V, a dominant-negative mutation, or no identified molecular etiology.
In the vascular form of EDS, mutations in COL3A1 may affect the synthesis, structure or secretion of type III collagen. The majority of mutations causing vascular EDS result in incorporation of an abnormal collagen type III (dominant-negative effect) with abnormal structure and secretion, although mutations in COL3A1 causing haploinsufficiency have also been associated with the phenotype of vascular EDS. Similar to classical EDS, there is no identifiable genotype-phenotype correlation between the type of mutation in COL3A1 and the phenotype in vascular EDS.
Systemic Implications and Complications
The ED syndromes are systemic conditions so a multispecialty approach is necessary for optimal management. Evaluation by specialists including geneticists, physical and occupational therapists, cardiologists, ophthalmologists, dermatologists, orthopedists, and gastroenterologists may be necessary.
Physical and occupational therapy are extremely important aspects of treatment of large and small joints respectively in EDS. The physical and/or occupational therapy will increase muscle tone surrounding hypermobile joints, preventing/alleviating subluxations/dislocations and acute or chronic pain (arthritis). It is crucial to continue indefinitely as part of the routine of daily life. The therapists should provide a home exercise program for the patient, with re-evaluation at regular intervals. Exercises (swimming and other low impact sports) that do not put undue impact on the joints are encouraged.
Avoidance of contact sports (such as volleyball, basketball, and American football), heavy lifting, weight training, jumping from heights, aerobics, acrobatics, gymnastics, and point ballet is important to help protect hypbermobile joints. Assistive devices such as specific joint bracing; orthotics (shoe inserts or braces) provide support for flat arches and pronated feet, preventing pain and discomfort in lower limbs.
Cardiology evaluation including electrocardiogram and echocardiogram, particularly in adults.
MedicAlert device stating diagnosis, especially for vascular EDS and classical EDS.
–Gastritis and gastro-esophageal reflux require proton pump inhibitors. An example is omeprazole or lansoprazole.
–Delayed gastric emptying requires pro-motility agents such as metoclopramide
–Irritable bowel syndrome requires antispasmodic medications, anti-diarrheal medications and laxatives.
–Chronic constipation requires high fiber diet, clear fluids, abdominal muscle strengthening, and routine toilet regimen.
–Enemas should NOT be used (can tear bowel wall).
–In a recent multicenter, randomized trial a β1-androceptor antagonist with a β2-androceptor agonist action has been shown to lower the incidence of arterial dissections and rupture in vascular Ehlers-Danlos syndrome.
–Anti-inflammatory medications, non-steroidal, for severe pain in classic and hypermobile EDS, until the beneficial effects of physical and occupational therapies alleviate joint pain.
–Pain medications if joint pain is interfering with activities of daily life.
–Beta-blockade to control aortic enlargement: Atenolol (Tenormin) is used commonly; it is a selective β1 receptor antagonist (beta blocker) that does not pass through the blood-brain barrier, avoiding central nervous system side effects.
–Neurally mediated hypotension (POTS): increase sodium and water, beta blockade, fluorocortisone and/or stimulants.
–Desmopressin acetate (ddAVP) for severe bleeding
–Psychiatric – Refer to psychologist, psychiatrist, or primary care physician for further evaluation and possible use of antidepressants.
–Avoidance of elective surgery for vascular EDS
–Repair of arterial or bowel rupture of hysterectomy after uterine rupture during pregnancy (vascular EDS) is a medical emergency, with high mortality after surgery because of the friable vessels
–Orthopedic procedures should be postponed in favor of physical therapy and bracing when possible.
–Dermal wounds should be closed without tension, preferably in two layers.
–Other wounds: deep sutures should be applied generously.
–Cutaneous sutures are left in place twice as long as usual.
–Borders of skin adjacent to the wound should be carefully taped to prevent stretching of scars.
Optimal Therapeutic Approach for this Disease
Disease severity is variable among patients with the hypermobile and classical forms of EDS. Some patients have very little morbidity while others are more significantly affected. Very importatnt treatment for the hypermobile and classical forms of EDS includes continuous physical and occupational therapy. When guided by therapists experienced with EDS, there is essentially no risk to the patient. Improvement in symptoms is variable and usually takes several months for the patient to notice response to treatment.
Treatment for the dermatologic manifestations of EDS is primarily preventive in nature. In individuals with skin fragility, protective pads or bandages can be worn to avoid skin tears and bruising. Should an injury to the skin occur, special care, detailed above in “surgical treatment,” should be given to ensure appropriate healing and to assist in minimizing atrophic scar formation.
Ascorbic acid (vitamin C) may reduce bruising, but there is no objective or subjective evidence that it helps.
Prevention/Avoidance: see treatment options above
Computer: At school, computers will help when a child with lax finger joints tires from writing.
School bags: Children should not carry very heavy bags on shoulders because this could lead to dislocation or subluxation of the shoulder joints. A rolling book-bag would be preferable.
School books: If there are many heavy books, a second set should be kept at home.
EDS is variable, therefore management of each patient will vary. Evaluation by a clinical geneticist with experience in connective tissue disorders should be performed, at least for an initial evaluation and, if necessary, subsequent visits. Thorough history and physical examination, highlighting musculoskeletal, skin, cardiovascular, and gastrointestinal manifestations as well as an assessment of current pain and disability as a result of the condition, are all important in the initial evaluation of the patient.
Referral to physical and occupational therapists experienced in connective tissue disorders, for treatment of pain and weakness is essential in the management of the musculoskeletal aspects of EDS.
Standard care includes a baseline echocardiogram and electrocardiogram to evaluate for aortic root diameter and MVP and potential arrhythmia (the latter is rare). In our experience non-symptomatic children with normal baseline studies do not require repeat studies until late adolescence/early adulthood because most cardiovascular changes are reported in adults.
Patients with vascular EDS should be evaluated by a cardiologist for treatment with a β1-adrenoceptor antagonist and, if treated, closely monitored.
For patients with features of orthostatic intolerance and/or tachycardia, tilt-table testing may be useful in establishing a diagnosis. Appropriate treatment includes increasing intake of fluid and salt and slowly changing body positions from lying down to sitting to standing .
For patients with features of constipation, ensure appropriate diet of high fiber and fluid intake, a routine toilet regimen after a meal, physical therapy to strengthen abdominal muscles, and if necessary medication such as polyethylene glycol (MiraLax) to assist with bowel movements. If symptoms do not improve or there are other gastroenterologic symptoms, referral to a gastroenterologist may be warranted to investigate whether there are unassociated problems.
For patients with a history of prolonged bleeding, referral to a hematologist to test for an unassociated bleeding diathesis and possible treatment may be necessary.
Clinical genetic testing is available for all of the genes shown to be involved in the six types of EDS classified by the Villefranche nosology (Table I). Sequencing of TNXB, the gene that encodes tenascin X, is currently only available for clinical testing in Spain.
While genetic testing is available, diagnosis is generally based on clinical examination in some of the subtypes of EDS, particularly as rare or limited patients are identified with specific genetic alterations in the hypermobile form (TNXB and COL3A1). Referral to a clinical geneticist or genetic counselor with experience in connective tissue disorders is recommended if the patient is interested in genetic testing or if the referring physician determines testing may be warranted. Situations that may warrant genetic testing include family planning and medical management decisions. Prenatal genetic testing is available for some of the types of EDS; referral to a prenatal genetics group is necessary for appropriate genetic counseling and testing. We offer gene testing for vascular EDS and the arthrochalasia form of EDS to confirm the diagnosis and offer prenatal testing.
We do not do routine gene testing for classic hypermobile EDS unless an affected person indicates that they would use that information for terminating a pregnancy with an affected fetus.
We do not do gene testing of tenascin X for hypermobile EDS because mutations have been found in only a few people; furthermore, the test is not availble in North America.
Unusual Clinical Scenarios to Consider in Patient Management
A defining feature in multiple subtypes of EDS, tissue fragility of the skin, often results in atypical scarring and significant bruising. Non-accidental trauma has been suspected in individuals with EDS although less commonly than in other connective tissue disorders such as osteogenesis imperfecta. In cases where there is a subdural hemorrhage, particularly in conjunction with bruising, it is important to consider vascular EDS as a possible cause. Medical letters carried constantly or more conveniently, medical alert devices (bracelets, necklaces) stating the diagnosis of EDS should decrease undue suspicion of child abuse.
Pregnancy: pregnant women should be managed by high-risk obstetricians; women with vascular EDS should be informed at the time of diagnosis of the vascular form that a pregnancy carries a high risk of uterine rupture with consequent maternal death.
What is the Evidence?
Beighton, P, DePaepe, A, Steinmann, B, Tsipouras, P, Wenstrup, RJ. “Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1977”. Am J Med Genet. vol. 77. 1998. pp. 31-7. (The authors, all authorities in the field of connective tissue diseases, met to refine the classification of Ehlers-Danlos syndrome (EDS) based on developments in the understanding of the molecular and biochemical causes of EDS as well as expanded clinical experience with these conditions. This article reviews the classification of the six most common forms of EDS and includes information regarding inheritance, major and minor criteria, as well as etiology and special considerations where relevant for each of the six types.)
Byers, PH, Scriver, Beaudet Sly, Valle. “Disorders of collagen biosynthesis and structure”. The metabolic and molecular basis of inherited disease. 2001. pp. 1065-81. (The author, a renowned expert in the field of collagenopathies, reviews the biosynthesis of collagen and the diseases that result from altered structure and function of collagen (collagenopathies). EDS is one of many collagenopathies and the collagens involved in EDS are also implicated in other diseases and/or interact with other collagenopathies. Collagen is the most abundant protein found in humans, and the numerous diseases that result from an abnormal collagen differ greatly in mechanism and phenotype. The author provides extensive review of collagen disorders including EDS.)
Castori, M, Camerota, F, Celletti, C, Grammatico, P, Padula, L. “Ehlers-Danlos syndrome hypermobility type and the excess of affected females: possible mechanisms and perspectives”. Am J Med Genet A. vol. 152A. 2010. pp. 2406-8. (The authors examined the anecdotal notion that female patients with hypermobile EDS are more likely to be identified than male patients and the underlying reason for the skewed sex ratio. Accumulated data support the hypothesis that females are more likely to come to clinical attention even among families with multiple affected male relatives. Although the authors were able to support the hypothesis that female patients were more likely to be identified, the reason for the disparity among male and female patients is not well understood.)
Malfait, F, De Paepe, A. “Molecular genetics in classic Ehlers-Danlos syndrome”. Am J Med Genet C Semin Med Genet. vol. 139C. 2005. pp. 17-23. (The authors examine the molecular basis and genetic mechanisms for classical EDS. Approximately 50% of individuals with classical EDS have been identified to have a mutation in COL5A1 or COL5A2, which encode alpha and beta chains of type V collagen. The relatively low rate of mutation in individuals with classical EDS emphasizes the heterogeneous nature of the disorder. Rare causes of classical EDS, such as mutation in type I collagen, are also discussed. Finally, the authors discuss the benefits and limitations of molecular genetic testing for classical EDS.)
McDonnell, NB, Gorman, BL, Mandel, KW, Schurman, SH, Assanah-Carroll, A, Mayer, SA. “Echocardiographic findings in classical and hypermobile Ehlers-Danlos syndromes”. Am J Med Genet A. vol. 140. 2006. pp. 129-36. (The authors examined the cardiovascular findings in 38 patients with classical and hypermobile EDS. Two-dimensional echocardiography was performed on all patients with a clinical diagnosis of EDS over a 2-year period. The authors noted a relatively high rate of cardiovascular involvement with 24 of 38 patients having altered echocardiographic parameters and 5 of 38 patients with at least, mildly dilated aortic root or sinuses of Valsalva. In contrast to earlier studies, the authors found a low incidence (1/38) of MVP. Earlier studies have provided disparate results and recommendations regarding the risk of cardiovascular disease . The authors have an ongoing study to collect longitudinal data on patients with classical and hypermobile EDS.)
Pepin, M, Schwarze, U, Superti-Fuga, A, Byers, PH. “Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type”. N Engl J Med. vol. 342. 2000. pp. 673-80. (The authors, from the Universities of Washington [Seattle] and Zurich, are experts in collagen disorders, including EDS. This article provides a comprehensive review of 419 individuals with vascular EDS. Statistics from this article include survival, age at first disease complication, special consideration for children and pregnancy in vascular EDS, as well as a review of molecular data in the largest cohort of patients with vascular EDS reported thus far.)
Smith, LT, Schwarze, U, Goldstein, J, Byers, PH. “Mutations in the COL3A1 gene result in the Ehlers-Danlos syndrome type IV and alterations in the size and distribution of the major collagen fibrils of the dermis”. J Invest Dermatol. vol. 108. 1997. pp. 241-7. (The authors examined skin biopsies from 22 individuals with vascular EDS and confirmed heterozygous mutations in COL3A1. The COL3A1 mutations were further classified based upon the mutations effect on type III procollagen and collagen fibril morphology. Mutations in COL3A1 were found to have varying effects, which were dependent on the nature of the mutation, location within the COL3A1 gene and resultant sequence change. Finally, the authors examine the possible role of type III collagen in the formation of various tissues.)
Steinmann, B, Royce, PM, Superti-Furga, A, Steinmann, B, Royce, PM. “The Ehlers-Danlos syndromes”. Connective tissue and its heritable disorders. 2002. pp. 431e523(This chapter regarding EDS provides an encompassing overview of the subtypes of EDS, including photos and pathophysiology, in subtypes where available. Information regarding the history of EDS is provided giving the perspective on the evolving syndrome over time.)
Voermans, NC, Knoop, H, Bleijenberg, G, van Engelen, BG. “Pain in Ehlers-Danlos syndrome is common, severe, and associated with functional impairment”. J Pain and Symptom Manage. vol. 40. 2010. pp. 370-8. (The authors, from Nijmegen Medical Center, are neurologists and chronic fatigue specialist who evaluated the impact of pain and fatigue in patients with EDS from the Dutch EDS patient organization using a series of questionnaires, profiles, and scales. They found that pain is a prevalent part of EDS and is associated with functional impairment of daily life, a disease manifestation identified by other authors as well and observed frequently in our clinical experience.)
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