Overview of the management of Ehlers-Danlos syndromes

INTRODUCTION — Ehlers-Danlos syndrome (EDS) is the term used for a group of genetic disorders of connective tissue that are characterized by skin hyperextensibility, joint hypermobility, and/or tissue fragility (table 1). The management of patients with EDS depends largely upon common principles and practices, with an emphasis on patient education for the prevention and early recognition of injuries and complications. Management of EDS also includes monitoring and additional interventions tailored to the particular manifestations or complications that may occur with each form of EDS [1].

There are no medical treatments that can reverse or "cure" EDS, and most other interventions used in these patients have not been evaluated in randomized trials. (See 'Common management approaches' below and 'Management by EDS type' below.)

An overview of the approach to the management, monitoring, and prognosis of patients with EDS will be presented here. The information provided in this topic review is intended to allow primary care providers and other non-EDS specialists to educate and support patients with EDS and to coordinate care and referrals to appropriate specialists, depending upon the type and severity of EDS. Patients with EDS should be managed in collaboration with an expert in clinical genetics. (See 'When to refer' below.)

The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of the major forms of EDS, and a detailed discussion of the management of the joint hypermobility syndrome, are presented separately. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes" and "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder" and "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

COMMON MANAGEMENT APPROACHES — Some major issues are common to several or most forms of Ehlers-Danlos syndrome (EDS); the preventive management strategies and interventions for such issues are generally the same regardless of the EDS type, and are discussed in this section. The particular approaches specific to each type of EDS are described below. (See 'Management by EDS type' below.)

When to refer — The primary care provider should work collaboratively with the geneticist and other EDS specialists to coordinate care for the patient with appropriate consultants (eg, experts in cardiovascular, orthopedic, rheumatologic, dermatologic, and behavioral health care). Additionally, the clinical geneticist and other EDS specialists have a role in educating the other members of the health care team, given the relative rarity of these disorders in most practice settings. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Clinical manifestations and diagnosis'.)

Patient education — Patient education and counseling on several subjects is important in EDS management, and includes:

●Education of patients (and parents or caregivers where appropriate) regarding the nature of the disorder and the absence of a curative therapy.

●Genetic counseling about the mode of inheritance and risk of recurrence in the family (see "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Genetics and pathogenesis'). Principles of genetic counseling are described separately. (See "Genetic testing".)

●Counseling of female adolescents and adult women of childbearing age regarding the risks of pregnancy and childbirth. (See 'Reproductive options and pregnancy' below.)

●Counseling regarding strategies that may help to prevent or reduce symptoms of EDS, including musculoskeletal pain. (See 'Joint protection and function' below and 'Musculoskeletal pain' below.)

●Education to facilitate recognition of symptoms of potentially serious conditions that may require urgent medical attention. (See 'Worrisome symptoms' below.)

Patients with vascular EDS should be advised to obtain a medical alert device, such as a bracelet or necklace, which indicates their diagnosis and possible complications to facilitate appropriate emergency medical care. Other patients with risk of vascular and other acute events, including patients with the classical and kyphoscoliosis types (cEDS and kEDS), may also benefit from use of such a device. Patients in North America can enroll in MedicAlert by calling (800) 432-5372 or through the internet at www.medicalert.org (United States) and www.medicalert.ca (Canada). (See 'Worrisome symptoms' below.)

Some patients and families or caregivers, depending upon their interest, may benefit from involvement with a resource such as the Ehlers-Danlos Society (or a similar organization) that provides information and support to those affected by EDS.

Psychosocial and psychological support — We suggest that patients who experience difficulty coping with the physical limitations or pain posed by EDS be referred for appropriate psychological counseling and support. We try to help patients to maintain a positive attitude, follow recommendations for joint protection and pain management, and choose physical activities that are appropriate for their condition (see 'Joint protection and function' below and 'Musculoskeletal pain' below). Patients also benefit, in our experience, from reassurance that EDS may be associated with chronic pain, which is "real" and not "all in their head."

Many patients may be adversely affected by the limitations posed by EDS (eg, those whose work or recreational activities requires heavy lifting). Patients who have pursued activities enhanced by their hypermobility (eg, professional ballerinas, competitive dancers, gymnasts, college athletes dependent upon sports scholarships) may be in particular need of psychosocial support.

Patients with chronic pain, anxiety, and depression, which are more common in individuals with joint hypermobility, may benefit from a multidisciplinary treatment program emphasizing functional recovery that includes cognitive behavioral therapy techniques, physical therapy, and education regarding their condition [2]. Such strategies may help to improve physical function, self-efficacy, and mood, and may reduce the need for analgesics. Participation in psychotherapeutic group interventions may also improve patient wellbeing. As an example, in one study a group of 12 women with generalized joint hypermobility were offered interventions including physical and cognitive-behavioral therapy as a group program; this program included an inpatient rehabilitation program with testing, physical therapy, group discussions, and lectures, followed by in-home physical therapy, then a brief inpatient stay for testing and retraining [3]. Participants reported improved performance of daily activities, increased muscle strength and endurance, and decreased kinesophobia (fear of movement and injury or re-injury), although self-reported pain levels were not significantly changed. (See "Overview of psychotherapies", section on 'Cognitive and behavioral therapies' and "Overview of psychotherapies", section on 'Group therapy'.)

Since anxiety and other neuropsychological conditions appear to be increased in EDS, assessment for these is required [4].

Joint protection and function — Patients with joint hypermobility should be referred for physical and occupational therapy evaluation and management; in addition, we advise patients regarding steps they can take on their own to optimize function, relieve symptoms, and prevent injury (table 2). An important objective for many patients, particularly those with the classical and hypermobility forms of EDS, should be to "preserve and protect" joint function, with the goal of preventing recurrent joint dislocations, chronic joint pain, and early onset of osteoarthritis. Prevention is of particular value because orthopedic procedures and other surgery may take longer than expected to heal, and many patients undergo repeated orthopedic procedures as their connective tissues increase in laxity [5]. The complication rate and surgical outcomes for patients with EDS undergoing orthopedic procedures appear to be worse than for non-EDS patients. In one study, a complication rate of 91 percent, including continued pain, subluxations and dislocations, instability, pain associated with hardware, and increased infections has been reported [6].

A low-impact muscle-strengthening program for joint protection and appropriate use of assistive devices (such as a cane or lightweight collapsible walking stick; or lightweight orthoses, such as braces or splints) can be of particular benefit. Evaluation by a pedorthist or podiatrist is of benefit to assess the need for arch supports or other orthotics. In one series of 79 patients in Belgium with hypermobile EDS, of the half who were enrolled in a physical therapy program, 63 percent reported benefit [7]. Patients with hypermobile EDS reported improved quality of life after physical therapy, especially the effect of respiratory muscle training on their exercise capabilities [8].

Patients can take a number of precautions and other actions in their daily activities, including measures to optimize function, relieve symptoms, and prevent injury (table 2), in addition to participating in physical and occupational therapy. These measures should be individualized according to the patient's clinical manifestations. Activities which are joint-sparing, such as swimming, should be encouraged; by contrast, contact sports and repetitive activities which stress the joints, such as running and weightlifting, should be avoided. Patients may also be attracted to activities in which their flexibility is a particular advantage, such as gymnastics, but these activities increase the risk of joint injury and earlier development of arthritis. For patients with EDS, the opposite of "no pain, no gain" is true; sports and activities which may have already contributed to joint damage at the time of diagnosis should be replaced with noncompetitive biking, swimming, and walking. Additionally, patients with substantial joint laxity and/or recurrent dislocations should avoid carrying items weighing more than about 5 pounds (about 2.25 kg). These strategies are useful, in our experience, but have not been systematically evaluated in clinical trials.

"Mind-body" techniques, such as tai chi, may also be useful for enhancing function and reducing pain. Although they have not been systematically evaluated inpatient with EDS, they appear to be helpful in patients with other disorders, such as fibromyalgia and low back pain. (See "Exercise-based therapy for low back pain" and "Treatment of fibromyalgia in adults", section on 'Increasing physical activity and exercise'.)

Musculoskeletal pain — In patients with joint hypermobility, preventive strategies and nonopioid pain management are important in the management of musculoskeletal pain, which may become chronic and difficult to treat. Pharmacologic treatment of joint pain involves the use of acetaminophen and, if necessary, nonsteroidal antiinflammatory drugs (NSAIDs); but the latter agents, which may diminish platelet function, should generally be avoided in patients with easy bruising.

Some patients with chronic musculoskeletal pain benefit from use of meditation or other relaxation techniques. Those with symptoms and findings compatible with fibromyalgia syndrome, such as chronic widespread pain, fatigue, nonrestorative sleep, and cognitive disturbance, may benefit from treatments used in this condition. (See "Clinical manifestations and diagnosis of fibromyalgia in adults" and "Treatment of fibromyalgia in adults" and "Fibromyalgia in children and adolescents: Treatment and prognosis overview".)

In one study, pain management strategies perceived as most effective by patients with EDS included massage therapy, splints or braces, and heat therapy [9]. Other strategies included using regular exercise, diet management (to avoid excess weight), avoidance of potentially harmful activities, and counseling. Physical therapy was used more by patients with hypermobile EDS than by those with classical or vascular forms of EDS. In addition, patients viewed pharmacologic treatment, especially with opioids, as effective.

Patients with refractory pain may require referral for further evaluation in a pain clinic. (See "Approach to the management of chronic non-cancer pain in adults".)

Some patients with EDS, such as those with symptoms of Raynaud phenomenon (especially cold or painful hands and feet), feel better in warmer, more humid climates and may benefit from medical therapy for Raynaud phenomenon. (See "Treatment of Raynaud phenomenon: Initial management" and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)

Fatigue — Several factors may contribute to fatigue in patients with EDS, including chronic musculoskeletal pain (see 'Musculoskeletal pain' above). In addition, sleep-disordered breathing may occur frequently in patients with EDS and may be under-recognized and a possible cause of fatigue [10], and there is an increased frequency of obstructive sleep apnea in this population [8]. This should be considered in the care of EDS patients; if suspected, patient should be referred to a sleep specialist for further evaluation. (See "Approach to the adult patient with fatigue" and "Mechanisms and predisposing factors for sleep-related breathing disorders in children".)

Skin fragility, wound management, and easy bruising — Special precautions may be required for wound healing in patients with hyperelasticity or fragility of skin (eg, classical and vascular EDS), but none of these techniques have been evaluated in randomized trials (see 'Classical EDS' below and 'Vascular EDS' below). The following approaches may be useful, according to experts and in our experience [1]:

●Because wound healing is abnormal and there is an increased risk of dehiscence, experts generally suggest that skin wounds should be closed in two layers, when possible, and there should be generous suturing of deep wounds to aid in wound healing. Sutures should generally remain in for twice as long as is typical for a given procedure. Taping can help prevent stretching of the scar.

●Individuals with significant skin fragility, particularly children, may decrease the risk of developing skin lacerations by the use of protective bandages or pads over especially exposed areas, such as the knees, shins, and forehead.

●Patients with easy bruising should avoid heavy exercise, contact sports, and the use of medications that may decrease platelet function, such as aspirin and most NSAIDs.

●For patients with easy bruising or skin fragility, the use of vitamin C (in doses ranging from 1 to 4 grams daily in adults) has been advocated by some experts in an effort to decrease bruising and improve wound healing, especially in patients with the kyphoscoliosis and vascular types of EDS, although this approach has not been formally tested [1,11,12]. Some experts also suggest vitamin C in patients with hypermobile EDS as well, but limit the dose of vitamin C to 500 mg daily in such patients [13]. However, there are no data to assess its effectiveness.

Worrisome symptoms — Certain symptoms should prompt suspicion for potential serious complications of EDS. These include:

●Sudden onset of pain or bleeding – Patients with EDS who experience sudden, unexplained onset of pain or bleeding should immediately undergo emergency evaluation, given their increased risk for and the catastrophic consequences of organ or vascular rupture. Such events are most commonly seen in patients with vascular or kyphoscoliosis EDS and may affect any part of the vascular tree, especially midsized arteries in the thorax and abdomen, as well as hollow or solid organs, most often the sigmoid colon, liver, spleen, and gravid uterus [14]. Vascular events can rarely occur in patients with classical EDS and in the other rare types of EDS [15]. (See 'Vascular EDS' below.)

●Sudden onset of dyspnea – Patients with a sudden onset of dyspnea should be evaluated for the possibility of a pneumothorax. (See "Pneumothorax in adults: Epidemiology and etiology" and "Spontaneous pneumothorax in children".)

●Orthostatic intolerance – Patients with orthostatic symptoms should be evaluated emergently to determine if hypovolemia from an acute vascular event is present, or whether symptoms have an alternative explanation, such as "drop attacks" (due to low blood pressure) and postural orthostatic tachycardia syndrome (POTS), which are a result of autonomic dysfunction. (See "Postural tachycardia syndrome".)

●Visual loss – Patients who experience sudden onset of visual "blind spots" or silvery flashes should be evaluated for retinal detachment. (See "Retinal detachment".)

●Acute chest pain – Acute chest pain may be a sign of an acute vascular or cardiac event, but costochondritis and rib-sternal subluxations due to EDS can each be confused with the chest pain of an acute myocardial infarction or other cardiovascular event. (See "Clinical evaluation of musculoskeletal chest pain", section on 'Ribs and chest wall examination' and "Major causes of musculoskeletal chest pain in adults" and "Management of isolated musculoskeletal chest pain".)

MONITORING — Preventive care and strategies to identify potential problems includes monitoring for disease manifestations that may not present symptomatically in their early stages. We suggest monitoring of most patients by experts in cardiovascular disease and ophthalmology, and monitoring of patients with symptoms or findings of spine disease by an expert in these conditions. (See 'Cardiovascular' below and 'Ophthalmologic' below.)

Cardiovascular — Patients with Ehlers-Danlos syndrome (EDS) should undergo cardiovascular evaluation, including echocardiography, for detection of cardiovascular involvement, including cardiac valvular and vascular disease, and aortic dilatation. There are no standardized protocols for such evaluation and monitoring in EDS. (See "Echocardiographic evaluation of the aortic valve" and "Natural history and management of chronic aortic regurgitation in adults" and "Mitral valve prolapse: Clinical manifestations and diagnosis" and "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet".)

We and other experts in EDS generally obtain baseline screening echocardiography in all patients, both children and adults, and take the following further steps, depending upon the findings, type and severity of EDS, and the preferences of the consulting cardiovascular disease specialist [13,16,17]:

●In patients with classical and hypermobile EDS, follow-up examinations are generally performed approximately every two to five years if initial studies are normal.

●In those patients whose second echocardiogram is also normal, the frequency of examinations can usually be decreased in the absence of new symptoms to every five years [13,16]. In adults with classical and hypermobile EDS, no further testing is usually needed beyond age 25 if the baseline evaluation and one follow-up examination are normal.

●Closer monitoring may be required in patients with vascular and kyphoscoliosis EDS, given the higher risk of cardiovascular diseases in these types of EDS, depending upon the severity of the illness. As examples, in patients in whom the aortic diameter is at the upper limit of normal on initial echocardiographic assessment, a repeat study should be performed in one year, while those with an increasing aortic root diameter should be reevaluated by the cardiovascular disease consultant.

●In patients with abnormal findings, consultation with an expert in cardiovascular disease should be obtained for further evaluation and follow-up, and to determine whether medication such as beta-blockade, celiprolol, or angiotensin receptor blockers are indicated to help prevent further aortic dilation. (See 'Vascular EDS' below.)

Ophthalmologic — Regular ophthalmologic examinations should be performed in all patients with EDS. Such examinations help to detect early retinal or scleral fragility, myopia, and glaucoma. Ophthalmologists typically perform such examinations on an annual basis. Patients with the kyphoscoliosis form of EDS are at the higher risk of scleral fragility, rupture of the ocular globe, keratoconus, retinal detachment, and glaucoma, compared with other forms of EDS. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Kyphoscoliotic EDS'.)

Allergies, mast cell activation, and immunodeficiency — Increased symptoms of mast cell activation disease (such as asthma, urticaria, flushing, and gastroenteritis) and hypogammaglobulinemia have been reported in patients with EDS [18], and it has been hypothesized that mast cell activation may underly the symptoms of some patients with hypermobile EDS [19]. Some experts have suggested that during the evaluation of patients with EDS, screening for mast cell activation and immunodeficiency be performed [18].

Scoliosis/spinal disease — Patients with EDS who develop scoliosis, peripheral neuropathy, or new neck pain should be evaluated and monitored as needed by an expert in spine care. Patients with kyphoscoliosis EDS are at particular risk of developing clinically significant scoliosis, but scoliosis can be seen in other forms of EDS, including classic, hypermobility, and arthrochalasia EDS, and may require intermittent use of braces or even surgical fusion [5,20,21]. Complications are higher in surgical treatment of EDS patients with scoliosis and careful monitoring of blood pressure and bleeding is critical. Evaluation for cervical spine instability with cervical spine flexion/extension films and magnetic resonance imaging (MRI) may be indicated. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes" and "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Classical or classic EDS' and "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Hypermobile EDS' and "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Kyphoscoliotic EDS' and "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Arthrochalasia EDS'.)

Anesthetic and perioperative management — Patients with EDS who undergo surgical procedures should receive care from providers and facilities with knowledge of EDS. Management will differ by type of EDS and the severity of disease, but several general principles apply [22]. These include:

●Careful preoperative evaluation and determination of the EDS type, which is critical for proper care.

●Assessment of bleeding history, cardiovascular history, and difficulties with intubation and wound healing.

●Use of noninvasive monitoring whenever possible.

●Careful attention to patient positioning for the procedure, with appropriate padding and caution with the use of tourniquets in those with tissue fragility.

●Careful fluid monitoring and blood pressure control throughout the pre-, intra-, and postoperative periods.

●Attention to difficulties with airway management, which are more frequent than in the general population, including potential bleeding, tissue damage, and joint dislocation.

●Careful assessment of patients with temporomandibular dysfunction and cervical spine instability.

●Management of bleeding, which should be individualized. Some patients benefit from use of desmopressin.

●Local anesthesia may be less effective in some patients [23].

MANAGEMENT BY EDS TYPE — The management strategies required in patients with Ehlers-Danlos syndrome (EDS) differ to some degree between EDS types, and should be individualized depending upon the severity of disease and the specific manifestations caused by the underlying genetic disorder. Some of these issues will impact the approach to usual medical care for other comorbid illnesses. Other management strategies may be common to most forms of EDS, but should still be tailored to the type of EDS and individual manifestations. (See 'Common management approaches' above and 'Monitoring' above.)

Classical EDS — The following concerns require particular attention in the management of classical EDS [12]:

●Musculoskeletal preventive care and symptom management. (See 'Joint protection and function' above and 'Musculoskeletal pain' above.)

●Physical therapy, including non-weightbearing exercise in children with hypotonia. (See 'Joint protection and function' above.)

●Measures for the prevention and management of skin fragility, wound healing, and easy bruising. (See 'Skin fragility, wound management, and easy bruising' above.)

●Emergency evaluation of patients with sudden onset of pain or bleeding. (See 'Worrisome symptoms' above.)

●Monitoring for the development of cardiac valvular disease and for aortic dilatation. (See 'Cardiovascular' above.)

●Gastrointestinal symptoms. Symptoms of esophagitis, gastroesophageal reflux, stomach upset, and irritable bowel syndrome are common and are treated in the same manner as in patients without EDS, but with attention in patients who undergo endoscopy to the fragility of tissues. (See "Medical management of gastroesophageal reflux disease in adults" and "Approach to the adult with dyspepsia" and "Treatment of irritable bowel syndrome in adults".)

●Pregnancy management, which is described separately. (See 'Reproductive options and pregnancy' below.)

●Monitoring of bone density. Decreased bone density has been noted in patients with EDS, although it is not clear whether it is intrinsic to EDS or to other factors such as decreased physical activity [24]. There are no specific recommendations for screening.

●Postural orthostatic tachycardia syndrome (POTS) and dysautonomia. The approaches to the evaluation and management of POTS and other dysautonomic syndromes are described separately. (See "Mechanisms, causes, and evaluation of orthostatic hypotension" and "Treatment of orthostatic and postprandial hypotension" and "Postural tachycardia syndrome".)

Hypermobile EDS — The management of hypermobile EDS, the most common of these disorders, is discussed in detail separately (see "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder"). The following concerns require particular attention (table 2) [13,25]:

●Musculoskeletal preventive care and symptom management. (See 'Joint protection and function' above and 'Musculoskeletal pain' above.)

●Physical therapy, with particular attention to low-impact, low-resistance exercise for strengthening of core and extremity muscles and joint stability. Patients should avoid resistance or isometric exercise, which can increase joint strain particularly if such exercise worsens symptoms.

●Monitoring for the development of cardiac valvular disease and for aortic dilatation. The approach to monitoring for valvular heart disease is usually the same as for patients with classical EDS. (See 'Cardiovascular' above.)

●Gastrointestinal symptoms. Symptoms of esophagitis, gastroesophageal reflux, stomach upset, and irritable bowel syndrome are managed as described for classical EDS.

●POTS and dysautonomia are managed as described for classical EDS. (See 'Classical EDS' above.)

Vascular EDS — Patients with the vascular form of EDS should be seen in consultation by an expert in cardiovascular disease and may benefit from joint follow-up with the consultant for cardiovascular surveillance. The following concerns require particular attention in the management of vascular EDS [14,17,26,27]:

●Emergency evaluation of patients with sudden onset of pain or bleeding. Patients with any sudden onset of pain or bleeding should be evaluated emergently, given the potentially catastrophic nature of organ or vascular rupture. (See 'Worrisome symptoms' above.)

●Prevention and management of vascular rupture. Patients with vascular EDS should be followed by an expert in cardiovascular disease, as some experts recommend vascular surveillance using noninvasive measures (ultrasound, magnetic resonance imaging [MRI], or computed tomography [CT], with or without venous contrast) for the detection of asymptomatic aneurysms and dissections, and the use of drugs such as beta-blockers or losartan [17] (see 'Cardiovascular' above). Baseline echocardiography and CT angiography (CTA) or MR angiography (MRA) imaging of the vasculature (head, neck, chest, abdomen, and pelvis) has been recommended at the time of diagnosis [28].

There have been several trials on the use of celiprolol, a long-acting beta-1 adrenoreceptor antagonist and partial beta-2 agonist, in reducing the occurrence of major arterial rupture or dissection in vascular EDS [29]. One study showed a 4.7 percent risk of a significant vascular event in treated individuals compared with 12 percent in controls [30]. Celiprolol is not approved for use by the US Food and Drug Administration (FDA) in the United States.

●Avoidance of vascular trauma. Patients should generally avoid arterial and intramuscular punctures, as well as arteriography given the high complication rate and risk of mortality, unless required preoperatively to identify a source of bleeding [14,17,27]. Endovascular procedures, where feasible, may have lower risks compared with open surgery, but data are limited to small case series, and estimates of mortality risk in patients requiring such procedures range from about 25 to 50 percent [14,27,31].

●The use of fluoroquinolone antibiotics should be avoided as these medications have been associated with an increased risk for aortic dissections, tendonitis, and tendon rupture [32-34]. (See "Fluoroquinolones", section on 'Aortic aneurysm and dissection'.)

●Measures for the prevention and management of skin fragility, wound healing, and easy bruising. (See 'Skin fragility, wound management, and easy bruising' above.)

●Measures for the prevention and management of bowel rupture. We and other experts do not ask patients to undergo baseline gastrointestinal evaluation because specific factors have not been identified that help in prediction of bowel rupture [17]. Routine colonoscopy should be avoided because of the risks of colonic perforation; virtual colonoscopy should be avoided because of the use of insufflation, which may also increase such risks; and alternative noninvasive measures for cancer screening, such as testing for occult blood, should be employed [17]. (See "Screening for colorectal cancer: Strategies in patients at average risk".)

●Reproductive-age females with vascular EDS should receive counseling to assure understanding of the high risk for uterine and vascular ruptures in pregnancy. (See 'Reproductive options and pregnancy' below.)

Kyphoscoliosis EDS — Patients with the kyphoscoliosis form of EDS should be seen in consultation by an expert in orthopedic management of spine disease and may benefit from joint follow-up with the consultant. The following concerns require particular attention in the management of kyphoscoliosis EDS [35]:

●Management of kyphoscoliosis. Patients should undergo orthopedic spine consultation and follow-up for care of the scoliosis, in part to prevent development of restrictive lung disease. (See 'Scoliosis/spinal disease' above.)

●Musculoskeletal preventive care and symptom management, including physical therapy for strengthening of large muscle groups, especially the shoulder region, and bracing of unstable joints. (See 'Joint protection and function' above and 'Musculoskeletal pain' above.)

●Cardiovascular evaluation and follow-up. Particular attention should be given to maintaining blood pressure control, and patients should undergo evaluation with echocardiography at the time of diagnosis or by age five, then every two to five years (or more frequently as indicated if abnormalities are present) to detect aortic root dilatation, for which beta blockers may be prescribed, as in patients with other aortic aneurysmal disease (see 'Cardiovascular' above and 'Vascular EDS' above) [35]. A high level of suspicion should be maintained for spontaneous arterial dissection in patients in whom symptoms are present that could be compatible with this condition.

●Measures for the prevention and management of skin fragility, wound healing, and easy bruising. Patients with kyphoscoliosis EDS may be treated with vitamin C (2 to 4 g daily), consistent with expert opinion, although the benefits of this intervention have not been formally evaluated, and this practice is not universal [1,11,12]. (See 'Skin fragility, wound management, and easy bruising' above.)

●Avoidance of vascular surgical trauma. Similar precautions to those employed for vascular EDS are suggested by experts, although published clinical experience is lacking [35]. (See 'Vascular EDS' above.)

●Ophthalmologic care. Patients should be followed by an ophthalmologist for ongoing ophthalmological care with particular attention to high myopia and/or astigmatism, and early detection of glaucoma, retinal detachment, microcornea, and scleral fragility. (See "Refractive errors in children" and "Visual impairment in adults: Refractive disorders and presbyopia" and "Retinal detachment".)

Other rare forms of EDS — Patients with the arthrochalasia and dermatosparaxis forms of EDS, as well as other rare forms, are managed symptomatically and as described for the other forms, depending upon their clinical manifestations. (See 'Monitoring' above and 'Management by EDS type' above.)

REPRODUCTIVE OPTIONS AND PREGNANCY

Counseling and genetic testing — Patients should be provided with appropriate education, counseling, support, and medical consultation to help facilitate individualized decision-making regarding pregnancy and family planning. Patients should also receive genetic counseling regarding the risk to their potential children of Ehlers-Danlos syndrome (EDS), and regarding additional testing which may be of benefit in aiding decision-making. (See "Genetic testing".).

In those in whom the DNA mutation is known, preimplantation genetic diagnosis (PGD) or prenatal diagnosis may be performed. In general, first-trimester DNA testing is by chorionic villus sampling (CVS), and second trimester testing is by amniocentesis. Caution should be taken with these invasive procedures in patients with EDS given the risk of serious maternal and fetal complications such as bleeding, separation, and rupture of membranes [36,37]. Intrauterine treatment or prevention is not available for the fetus. (See "Chorionic villus sampling" and "Diagnostic amniocentesis".)

Pregnancy, delivery, and postpartum care — Premature delivery due to cervical insufficiency or premature rupture of membranes is common, and patients with EDS should be considered at high risk and followed by a maternal-fetal-medicine specialist [38]. Patients with classical EDS should be monitored during the third trimester for preterm labor, given the risk of premature rupture of the membranes [12]. (See "Preterm prelabor rupture of membranes: Clinical manifestations and diagnosis".)

The following issues are also of concern in women with EDS:

●Labor and delivery may progress rapidly in patients with the hypermobility form of EDS, but there is no clear advantage to either vaginal or Cesarean delivery [13].

●Patients with vascular EDS are at high risk for uterine and vascular ruptures; pregnancy mortality for vascular EDS is estimated at 12 percent, and it is uncertain which mode of delivery might have any less or greater risk in such patients [38]. Patients with vascular EDS should be under the care of an obstetrician with subspecialty expertise in maternal-fetal medicine during pregnancy. Survival data in one study indicated that pregnancy did not appear to affect overall mortality, compared with nulliparous women with vascular EDS, advising shared decision-making in women with vascular EDS contemplating pregnancy and pregnancy management [39].

The 2018 European Society of Cardiology (ESC) guidelines for the management of cardiovascular diseases during pregnancy describe pregnancy for patients with vascular EDS as a "very high-risk undertaking" that is not advised, recommending shared decision-making for those women with vascular EDS who contemplate pregnancy [40]; the ESC also suggests use of the beta blocker celiprolol throughout pregnancy in women with thoracic aortic disease associated with vascular EDS. (See 'Vascular EDS' above.)

●Ligamentous laxity and tendon rupture can complicate the third trimester in patients with most types of EDS.

●After delivery, postpartum hemorrhage, extension of episiotomies, and uterine and bladder prolapse can occur; patients with the classical and vascular forms of EDS are at greatest risk. (See "Uterine rupture: Unscarred uterus" and "Overview of postpartum hemorrhage" and "Effect of pregnancy and childbirth on urinary incontinence and pelvic organ prolapse".)

Patients with chronic postpartum dyspareunia should be evaluated for occult prolonged diastasis of the pubic symphysis, as painful postpartum separation of the pubic symphysis may require surgical repair.

It has been recommended that spinal or epidural anesthesia techniques be avoided in patients with vascular EDS [22].

PROGNOSIS — Ehlers-Danlos syndrome (EDS) generally results in slowly progressive changes. The prognosis depends upon the type of EDS and the severity with which the individual patient is affected, which varies. The degree of joint difficulty, frequency of recurrence of joint dislocations, and intensity of pain correlate with activities.

Survival can vary based upon the type of EDS and associated morbidities:

●The lifespan for patients with the classical and hypermobility forms is not decreased.

●In vascular EDS 80 percent of individuals experience a major event by age 40 years [26], and there is a shortened lifespan with a median age of death of 48 years [41].

●The lifespan of patients with the kyphoscoliosis form is also decreased, due to the vascular involvement and potential for restrictive lung disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ehlers-Danlos syndromes and joint hypermobility".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Ehlers-Danlos syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Patients with Ehlers-Danlos syndrome (EDS) should be cared for in close collaboration with an expert in clinical genetics and other EDS specialists, including experts in cardiovascular disease, orthopedic surgery, ophthalmology, and behavioral medicine, depending upon the type and severity of EDS and the specific clinical manifestations. Patient education and counseling includes the nature of the condition and absence of cure; strategies for the recognition, prevention, and reduction of symptoms; genetic counseling; and counseling regarding the risks of pregnancy and childbirth. (See 'Common management approaches' above and 'When to refer' above and 'Patient education' above and 'Psychosocial and psychological support' above.)

●Patients with joint hypermobility (eg, classical and hypermobile EDS) should be referred for physical and occupational therapy evaluation and management, and advised regarding steps they can take on their own to optimize function, relieve symptoms, and prevent injury (table 2). (See 'Joint protection and function' above and 'Musculoskeletal pain' above.)

●Special precautions may be required for wound healing in patients with hyperelasticity or fragility of skin (eg, classic, vascular, and kyphoscoliosis EDS), including closing wounds in two layers with generous suturing; keeping sutures in for twice as long as is typical; and prevention of injury with use of protective bandages or pads over exposed areas. Precautions in patients with easy bruising include avoidance of trauma or medications that increase the risk of bleeding and the use of vitamin C in selected patients, including those with the kyphoscoliosis and vascular types of EDS. (See 'Skin fragility, wound management, and easy bruising' above.)

●Symptoms that should increase suspicion of potential complications and indicate a need for urgent evaluation include sudden onset of unexplained pain, bleeding, or dyspnea; acute chest pain; orthostatic intolerance; and visual loss. (See 'Worrisome symptoms' above.)

●Patients with EDS should undergo baseline cardiovascular evaluation, including echocardiography, for detection of cardiac involvement, including valvular disease; and ophthalmologic examination. The frequency of monitoring depends upon the type of EDS and presence or absence of clinical findings. Patients with EDS who develop scoliosis, peripheral neuropathy, or new neck pain should be evaluated and monitored as needed by an expert in spine care. (See 'Monitoring' above.)

●The management strategies required in patients with EDS differ to some degree between EDS types, and should be individualized depending upon the severity of disease and the specific manifestations caused by the underlying genetic disorder. Some of these issues will impact the approach to usual medical care for other comorbid illnesses. Other management strategies may be common to most forms of EDS, but should still be tailored to the type of EDS and individual manifestations. (See 'Management by EDS type' above.)

●Patients should be provided with appropriate education, genetic and other counseling, support, and medical consultation to help facilitate individualized decision-making regarding pregnancy and family planning. Premature delivery due to cervical insufficiency or premature rupture of membranes is common, and patients with EDS should be considered at high risk and followed by a maternal-fetal-medicine specialist for these and other potential complications. Patients with vascular EDS are at high risk for uterine and vascular ruptures. (See 'Counseling and genetic testing' above and 'Pregnancy, delivery, and postpartum care' above.)

●EDS generally results in slowly progressive changes. The prognosis depends upon the type of EDS and the severity with which the individual patient is affected. The lifespan for patients with the classical and hypermobility forms is not decreased; by contrast, survival is shortened in forms of EDS with vascular involvement (eg, vascular and kyphoscoliosis EDS), and 80 percent of patients with vascular EDS experience a major adverse disease-related event by age 40. (See 'Prognosis' above.)