NORD gratefully acknowledges Xenia Chepa-Lotrea, NIH/National Human Genome Research Institute, MD candidate at Georgetown University School of Medicine, and Clair Francomano, MD, Director of Adult Genetics and Director the Ehlers-Danlos National Foundation Center for Clinical Care and Research, Greater Baltimore Medical Center, Harvey Institute for Human Genetics, for assistance in the preparation of this report.
The Ehlers-Danlos syndromes (EDS) are a group of related disorders caused by different genetic defects in collagen. Collagen is one of the major structural components of the body. Collagen is a tough, fibrous, protein, and serves as a building block essential in both strengthening connective tissue (e.g. bones) and providing flexibility where needed (e.g. cartilage). The problems seen in patients with EDS can be due to either the poor strength of collagen. It may alternatively be due to the absence of sufficient amounts of structurally normal collagen. The primary complications seen in EDS involve the skin, muscles, skeleton, and blood vessels. Patients with EDS often have skin that can be describes as “velvety”, “loose”. This skin characteristic predisposes patients to problems with wound healing. Patients will often note that they develop “paper-thin” scars. Patients also have excessively flexible, loose joints. These ‘hypermobile’ joints can be easily and frequently dislocated. Finally, fragile blood vessels leave patients experiencing easy bruising, even an increased tendency to serious episodes of bleeding.
Each subtype of EDS results from a distinct genetic change. Patients within a given, specific subtype share characteristics of disease beyond the primary problems described above, and are covered in detail below.
The named subtypes of EDS have undergone extensive reorganization as more information becomes available. EDS was originally categorized under eleven Roman numeral designations (EDS I -EDS XI), based primarily on symptoms and mode of inheritance. Later, EDS was classified into six subtypes based on the characteristic features of each type. In 2017, the International Classification for the Ehlers-Danlos Syndromes was published, in which thirteen descriptive subtypes are recognized. The 2017 International Classification most recently outlines a classification based on underlying genetic causes (Group A-F) that is used for research purposes.
cEDS (formerly EDSI and EDSII) is associated with the primary problems described above, skin hyperextensibility, joint laxity, and fragile blood vessels. Scars are very thin, discolored, and stretch with time. Such paper-like (papyraceous) scarring occurs especially over prominent bony pressure points such as the knees, elbows, shins and forehead. Joint hypermobility accidents (subluxations and dislocations) are generally easily managed. Additional findings may include the formation of small, fleshy, skin growths called ‘molluscoid pseudotumors’ or hard, round, movable lumps under the skin called ‘calcified spheroids’. Finally, some individuals with this subtype may have a deformity of heart valves (especially the mitral/bicuspid valve between the atrium and the ventricle of the left side). The heart’s valves function to keep blood flowing in one direction. Weak valves may be overcome by the blood flow across their leaflets and prolapse, allowing blood to leak in the backwards direction. Valve dysfunction can result in remodeling of the heart’s architecture and with time congestive heart failure (pump insufficiency). Another complication cEDS patients may experience is dilatation of the aorta. The aorta is the major blood vessel coming immediately off the heart, responsible for directing oxygenated blood towards body tissues. In cEDS there is an increased risk also for aortic dissection. Blood vessel walls are made up of three layers (intima, media, and the adventitia). Dissection describes the separation of the intima from the media and adventitia. This complication can compromise blood supply to tissues including the heart. Aortic dissection is an immediate emergency that can result in acute heart failure. Patients should immediately seek medical attention for any tearing chest pains.
clEDS is similar in clinical course to cEDS (described immediately above). Genetic causes of cEDS and clEDS differ (described below).
Cardiac-valvular type (cvEDS)
cvEDS is a rare subtype of EDS wherein patients may have minor signs of EDS with severe defects to their aorta, requiring surgical interventions.
Vascular type (vEDS)
vEDS (formerly EDSIV), can be identified at birth with noticeable clubfoot deformities and dislocation of the hips. In childhood, inguinal hernia (partial slip of intestine beyond the abdominal wall) and pneumothorax (collection of air between the lung and chest wall, impairing proper lung inflation) are commonly experienced and are indicative of this syndrome. Individuals with vEDS may also have abnormally decreased levels of fatty tissue under skin layers (subcutaneous adipose tissue) of the hands, arms, legs, feet, and face. Thus, some affected individuals may have a characteristic facial appearance. Cheeks are often taught and hollow. Lips and nose are often thin. Eyes are relatively prominent. In addition, skin of the hands and feet may appear prematurely aged (acrogeria). vEDS is particularly associated with arterial dissection and rupture, intestinal perforation, and uterine rupture. Arterial dissections are ruptures along the layers of tissue that comprise the thickness of the artery and may be spontaneous or preceded by an aneurysm (abnormal bulge in a vessel diameter) or arterio-venous malformation (AVM, abnormal connection between arteries and veins in the body). These bleeds can be life-threatening. One common AVM EDS patients experience is a carotid-cavernous sinus fistula. This is an abnormal connection between the carotid artery (a major offshoot of the aorta that supplies oxygenated blood to the brain) and the cavernous sinuses (a pool of deoxygenated blood deep within the skull behind the eyes). AVM can result in severe headaches, seizures, and increases a patient’s risk for stroke. There is an early onset of varicose veins, unusually widened, twisted veins visible under the skin that may be painful. vEDS carries a risk for spontaneous rupture of certain membranes and tissues. Acute pain in the abdominal or flank area may indicate arterial or intestinal rupture; such symptoms require immediate emergency medical attention. Pregnancies should be considered higher risk and watch closely for arterial and uterine ruptures. 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). The median life expectancy for vEDS is 50, but with careful surveillance and management of complications this age can be well extended.
Hypermobility type (hEDS)
hEDS (formerly EDSIII) comes with a defined set of complications to be managed but is generally a less severe form of the syndrome. For example, aortic root dilation is usually minimal and does not significantly increase the risk for dissections. The major complications to patients with hEDS are musculoskeletal in nature. Frequent joint dislocation and degenerative joint disease are common and associated with a baseline chronic pain, which affects both physical and psychological wellbeing. Problems with the autonomic nervous system, responsible for regulating body functions and the fight-or-flight response, are common. For example, patients often experience orthostatic intolerance, significant lightheadedness on standing, due to a slowed response by their circulatory system to compensation against blood pressure and flow changes with shifts in body position. Bowel disorders are also more common with this condition, especially functional dyspepsia (indigestion), and irritable bowel syndrome. Patients with EDS hypermobility type have also frequently reported psychological impairment and mood problems.
Arthrochalasia type (aEDS)
aEDS (formerly EDSVII, A and B) is associated with the lifelong risk for the dislocation of multiple major joints concurrently. This condition makes achieving mobility significantly challenging. It is important to identify as early in life as possible as it carries consequences of physical disability with older age. Newborns may demonstrate severe muscular hypotonia and a bilateral dislocation of the hips at birth and might be difficult to distinguish from kEDS (described below).
Dermatosparaxis type (dEDS)
Patient with dEDS (formerly EDSVIIC) tend to show a set of common body features. These include a short stature and finger length, loose skin of the face, with comparatively full eyelids, blue-tinged whites of the eye (sclera), skin folds in the upper eyelids (epicanthal folds), downward slanting outer corners of the eyes (palpebral fissures) and a small jaw (micrognathia). A major complication of dEDS is herniation, the improper displacement of an organ through the tissues holding it in proper position. Hernias are especially common after certain surgeries, for example wherein there is an incision into the muscles of the abdomen. Due to the lengthy wound-healing process, intestinal contents may bulge through incisions. Patients with dEDS are also prone to ruptures in the diaphragm and bladder. For families with a suspected history of dEDS type, the parents of newborns should be advised that their child’s soft spots in the skull (fontanelles) may be delayed in their closure.
Kyphoscoliotic type (kEDS)
kEDS is accompanied by scleral fragility, increasing the risk for rupture of the white globe of the eye. Microcornea, near-sightedness (myopia), glaucoma and detachment of the nerve-rich membrane in the back of the eye (retina) are common and can result in vision loss. Patients experiencing floaters, flashes or sudden curtains falling across their visual field should seek immediate medical attention. kEDS (formerly EDSVI) can be evident at birth. Newborns may demonstrate severe muscular weakness (hypotonia) or abnormal spinal rotations and curvatures (scoliosis). Despite progressive scoliosis, the survival of patients with kEDS is unaffected. The most severely affected adults may lose the ability to walk by their 20s-30s and it becomes important to watch that their scoliosis does not begin to impede normal breathing patterns.
Brittle cornea syndrome (BCS)
BCS is a variant of EDS that also involves the eyes. People with variant risk ruptures to the cornea following minor injuries with scarring, degeneration of the cornea (keratoconus), and protrusion of the cornea (keratoglobus). Patients may have blue sclera.
Spondylodysplastic type (spEDS)
spEDS, previously spondylocheirodysplastic type, describes an EDS variant with skeletal dysmorphology. It primarily involves the spine and the hands. Clinical presentation can include stunted growth, short stature, protuberant eyes with bluish sclera, wrinkled skin of the palms, atrophy of muscles at the base of the thumb (thenar muscles), and tapering fingers.
Musculocontractural type (mcEDS)
mcEDS is characterized by progressive multisystem complications. This subtype is especially associated with developmental delay and muscular weakness plus hypotonia. Patients often have facial and cranial structural defects, congenital contractures of the fingers, severe kyphoscoliosis, muscular hypotonia, club foot deformity, and ocular problems.
Myopathic type (mEDS)
mEDS is characterized by muscle hypotonia evident at birth with muscles that do not function properly (myopathy). Scoliosis and sensorineural hearing impairment may accompany this condition. It shares many features with the kyphoscoliotic form of EDS.
Periodontal type (pEDS)
pEDS type (formerly EDS VII) has findings that include disease of the tissues surrounding and supporting the teeth (periodontal disease), potentially resulting in premature tooth loss.
Some subtypes of EDS included within the original disease classification system have been redefined and are no longer part of the revised categorization (eg: previously known as EDS type IX has been redefined to occipital horn syndrome and EDSXI is now known as familial hypermobility syndrome). For more information on these disorders, please see the “Related Disorders” section of this report below.
EDS can be inherited as a dominant or recessive genetic condition. Human traits are the product of the interaction between two genes. Genes are received in sets of two, one from the father and another from the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
When someone in the family is diagnosed with EDS, it is important to contact a physician for further evaluation and to determine the mode of inheritance in the family.
Some of the genes associated with EDS provide the instructions on the synthesis of (encode) different subtypes of collagen (COL1A1, COL1A2, COL1A3, COL5A1, and COL5A2). Other genes (ADAMTS2, PLOD1, and TNXB) encode proteins associated with processing collagen or otherwise interacting with collagen. Defects in these genes have been associated with different EDS subtypes. Type-specific genetics are summarized below.
Classical type (cEDS)
cEDS follows an autosomal dominant inheritance pattern of inheritance for mutations on two genes: COL5A1 and COL5A2. COL5A1 encodes the protein ‘pro-alpha1(V)chain’ and COL5A2 encodes ‘pro-alpha2(V)chain’. The “pro-” designation indicates that their final product must be acted on by an enzyme which activates the final structure. Procollagen is the product of three chain-like proteins. Procollagen is processed by extracellular enzymes to a mature product. The final collagen product will associate into fibrils with type 1 collagen and function to determine the width of the type 1 collagen fibrils.
clEDS is follows an autosomal recessive inheritance pattern. It is caused by mutations in the gene TNXB. This gene product is found outside the cell and serves in maintaining the integrity of the scaffold in which the collagen lays down. Tenascin-x also functions to regulate the stability of the body’s elastic fibers.
Cardiac valvular type (cvEDS)
cvEDS is a rare subtype that follows an autosomal recessive inheritance pattern and is also associated with mutations in the COL1A2 gene. COL1A2 encodes pro-apha2(I)chain. Two pro-alpha1(I) chains (encoded by COL1A1) and one pro-apha2(I)chain (encoded by COL1A2) associate to form type 1 procollagen fibrils.
Vascular type (vEDS)
vEDS is inherited in an autosomal dominant manner and usually caused by mutations in the gene COL3A1. There have been some reports of bi-allelic inheritance, where an affected individual has two mutant genes. COL3A1 encodes pro-alpha1(III)chain. Three of these products associate to form type III procollagen. Mature type III collagen assembles into long, thin fibrils. Crosslinking lends important strength to this collagen subtype. Some patients with vEDS have COL1A1 gene mutations (described above).
Hypermobility type (hEDS)
hEDS follows an autosomal dominant inheritance pattern but the causal genes have not yet been unidentified. A small number of affected individuals have been found to have a deficiency of tenascin-x, a protein encoded by the gene TNXB. This gene product is found outside the cell and serves in maintaining the integrity of the scaffold in which the collagen lays down. Tenascin-x also functions to regulate the stability of the body’s elastic fibers.
Arthrochalasia type (aEDS)
aEDS follows autosomal dominant inheritance. This subtype is caused by mutations in the COL1A1 gene, or the COL1A2 gene. COL1A1 encodes pro-apha1(I)chain. COL1A2 encodes pro-apha2(I)chain (described above).
Dermatosparaxis type (dEDS)
dEDS follows an autosomal recessive inheritance pattern and is associated with mutations in the gene ADAMTS2. The enzyme encoded by this gene modifies collagen products. It cleaves short amino acid chains from procollagen molecules into mature collagen.
Kyphoscoliotic type (kEDS)
kEDS follows autosomal recessive inheritance and is caused by mutations in the PLOD1 or FKBP14 genes. Mutations in PLOD1 result in a deficiency of activity in the enzyme procollagen-lysine, 2-oxogluterate 5-dioxygenase 1, also known as lysyl hydroxylase 1. This hydroxylase enzyme converts the amino acid lysine into hydrolysine. Hydrolysine is a modified amino acid essential to forming cross-links between individual of collagen chains. The FKBP14 gene encodes FK506-binding protien-14, which does not have a clearly defined function in the cell.
Brittle cornea syndrome (BCS)
There are two types of BCS, both inherited in an autosomal recessive manner. Type 1 BCS is caused by mutations in the ZNF469 gene. Zinc finger protein 469 is thought to act as a DNA transcription factor or extra-nuclear regulator for collagen fiber synthesis or organization. Type 2 BCS is caused by mutations in the PRDM5 gene. The encoded protein, PR/SET domain 5, is a transcription factor regulating protein synthesis.
Spondylodysplastic type (spEDS)
spEDS is inherited as an autosomal recessive condition and is associated with mutations in the gene SLC39A13, encoding the protein product solute carrier family 39 member 13, responsible for the transport of zinc into the cell. Zinc is a metal element and essential to the healthy function of connective tissues. This subtype can also be attributed to genetic defects in the B4GALT6 and B4GALT7 genes. The beta-1,4-galactosyltransferase gene family is associated with the synthesis of different glycosylated and saccharide structures.
Musculocontractural type (mcEDS)
mcEDS follows autosomal recessive inheritance pattern and can be caused by mutations in two genes. Mutations in the gene CHST14, which encodes the enzyme carbohydrate sulfotransferase 14, is involved in several chemical reactions involving the transfer of sulfate groups between different molecules. mcEDS may also be caused by mutations to the gene DSE. The gene product, dermatan sulfate epimerase, is important in the production of dermatan sulfate (also known as chondroitin sulfate B), a glycosaminoglycan. Glycosaminoglycans are important in filling in connective tissue gaps, lending cohesion and stability.
Myopathic type (mEDS)
mEDS can follow an autosomal dominant or autosomal recessive pattern of inheritance. Mutations causing this subtype are found in the COL12A1 gene, encoding type XII collagen. This fibril is associated with type I collagen and is thought to modify the interactions it makes. mEDS can also be caused by mutations in the gene FKBP14. FK506-binding protien-14 does not have a clearly defined function in the cell.
Periodontal type (pEDS)
pEDS follows autosomal dominant inheritance and is caused by mutations in the genes C1R and C1S, encoding complement subcomponents, important to immune function.
Signs and symptoms of EDS may become apparent during childhood. However, depending upon the form and severity, age of diagnosis varies widely. Reported estimates for the incidence of all EDS types range from 1/ 2,500 to 1/5,000 births. hEDS is estimated to affect 1/10,000-1/15,000. cEDS is estimated to affect 1/20,000-1/40,0000. Because those with mild joint and skin manifestations may not seek medical attention they remain undiagnosed and it is difficult to determine the true frequency of EDS mutations in the general population. hEDS, clEDS, and vEDS are most common subtypes. Other subtypes (kEDS, aEDS, and dEDS) are much less common. Only about 60 individuals with kEDS have been identified. Only about 30 patients with aEDS have been reported. Only about 12 patients of dEDS have been described. Some named variants of EDS (e.g. X type or dysfibronectinemic type) have only been identified and reported in single individuals within one affected family.
EDS is generally diagnosed based on patient history and clinical findings. Genetic testing can facilitate the diagnosis of some subtypes. Electron microscopic analysis of tissue samples can also sometimes reveal characteristic abnormalities in collagen structure seen in EDS.
The clinical evaluation of individuals with suspected or diagnosed EDS typically includes assessments to detect and determine the extent of skin and joint hyperextensibility. For example, physicians may measure skin hyperextensibility by carefully pulling up skin at a neutral site until the point of resistance, and joint hyperextensibility may be evaluated using a clinical rating scale (i.e., Beighton scale). Often, specialized imaging tests, such as computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and echocardiography, are used to detect and characterize mitral valve prolapse and aortic dilatation. During a CT scan, a computer and x-rays create a film showing cross-sectional images of certain bodily structures. MRI uses a magnetic field to create cross-sectional images of organs and tissues. During an echocardiogram sound waves are directed toward the heart enabling physicians to study cardiac function and motion. In addition, in some individuals with EDS, specialized x-ray studies may be used to characterize round movable lumps (calcified spheroids) under the skin, to detect and determine the extent of abnormal spinal curvature (scoliosis and/or kyphosis) and/or reduced bone mass (ostepenia) (e.g., in those with EDS kyphoscoliosis or arthrochalasia types), and/or to confirm and characterize certain other abnormalities.
Genetic analysis is helpful in the diagnosis of many EDS subtypes, either in providing a positive finding (eg: mutations in COL5A1 for patients with cEDS) or negative finding. As the genetic source of hEDS is yet unidentified, it is important to rule out mutations that cause other EDS types. A kEDS diagnosis can also be confirmed by a laboratory test on either a urine sample and extrapolated ratio of deoxypyridinoline to pyridinoline cross-links, or on a skin biopsy sample and measurement of lysyl hydroxylase enzyme activity from skin fibroblast cells.
The care of patients with EDS is generally focused on implementing preventative measures against serious or life-threatening complications. The primary complications seen in EDS involve the skin, musculoskeletal, and cardiovascular systems. Patient skin is velvety thin, loose, and stretchable. This predisposes patients to difficulties with wound healing. For both accidental and surgical wounds, deep stiches are applied generously. Superficial stiches are placed to carefully realign the skin to prevent scarring. Stiches are also left in for extended periods of time to allow best strengthening of the forming scar tissue. Ascorbic acid (Vitamin C) may be recommended to help reduce the easy bruising that accompanies EDS. Hypermobile joints easily dislocate. With each dislocation, subsequent dislocations are increasingly likely, therefore prevention is particularly important for quality of life. Heavy sports, lifting, and other strenuous efforts should be avoided due to the risk of inciting trauma. Blood vessel fragility increases the risk for serious bleeds and dissections. High blood pressure (hypertension) puts additional strain on the fragile vasculature and increases the risk for complications. Regular screening for hypertension and arterial disease should be conducted and treatment should be initiated early on. The best approaches to screening are by non-invasive technology: ultrasound, MRI, or CT. Arteriography, colonoscopy, and other similarly invasive screening procedures should be considered carefully for benefit versus risk. Surgery for non-life threatening conditions should also be carefully considered. Pregnancies should be followed by obstetricians that are well trained in dealing with high-risk pregnancies. Delivery can progress very quickly in EDS patients and it is yet unclear if there is an advantage to mothers to deliver by vaginal or cesarean routes. Expectant mothers with known aortic root dilations should have echocardiograms each trimester to observe for possible exacerbation. All EDS-affected individuals should seek immediate medical attention for any sudden or unexplained pains and consider wearing a MedicAlert bracelet to communicate their status as a patient with EDS should they lose consciousness.
hEDS patients may especially benefit from physical therapy, low-resistance exercise, and assistive devices like braces, wheelchairs, and scooters. Comfortable writing utensils and a low-stress mattress serve an important role in reducing musculoskeletal pain. Pain management is tailored to the individual. Gastrointestinal and psychological complications are likewise managed per an individual’s needs. In addition to physical therapy and low-resistance exercise, calcium and vitamin D can help maximize bone density. DEXA bone density scans should be conducted every other year. kEDS patients should have routine eye exams as they are at risk for globus rupture, retinal detachment and glaucoma. dEDS patients may benefit from protective bandages over exposed areas such as the skin of the elbows and knees.
The Vascular Ehlers-Danlos (VEDS) Research Collaborative Study is a natural history study enrolling patients with genetically confirmed VEDS. https://www.vedscollaborative.org/get-involved
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. This site provides summaries and investigator contact information on both actively enrolling and completed clinical trials, with results where available.
New open trials and trial results are constantly being updated. Patients are encouraged to check postings regularly.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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Pepin MG, Murray ML, Byers PH. Vascular Ehlers-Danlos Syndrome. 1999 Sep 2 [Updated 2015 Nov 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1494/ Accessed September 27, 2017.
Yeowell HN, Steinmann B. Ehlers-Danlos Syndrome, Kyphoscoliotic Form. 2000 Feb 2 [Updated 2013 Jan 24]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1462/ Accessed September 27, 2017.
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