Author(s): Yuxi Chen, MD, Emilee Bell, DO, Jessi Yu, MD
Originally published: January 24, 2013 Last updated: May 8, 2024
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Disease/Disorder

Definition

Ehlers-Danlos syndrome (EDS) comprises a heterogeneous group of diseases with multi-systemic and variable clinical manifestations affecting primarily the skin, ligaments, joints, blood vessels and internal organs.1

Having 3 of the major diagnostic criteria is highly specific for classic type of EDS: skin hyperextensibility, widened atrophic scarring, joint hypermobility, and positive family history.

Minor diagnostic criteria include smooth velvety skin, molluscoid pseudotumors, subcutaneous spheroids, joint hypermobility complications, muscle hypotonia, delayed gross motor development, easy bruising, manifestations of tissue extensibility/fragility, and surgical complications.2

Etiology

EDS can be inherited as either autosomal dominant, autosomal recessive, or, rarely, X-linked. Fifty percent of the classical type have a de novo disease-causing mutation.3 Mutations in genes encoding fibrillary collagens or collagen-modifying enzymes are responsible for the syndrome; however, the exact molecular defect has not been identified for every type of EDS.

Epidemiology including risk factors and primary prevention

The actual prevalence of EDS is unknown, because many patients fail to be diagnosed, particularly if they demonstrate only a single symptom of the syndrome. The incidence may be as high as 1 in 5000 births, with no ethnic or racial predisposition.2,3

Patho-anatomy/physiology

Genetic defects affecting the biosynthesis and structure of collagen type I, III and V have been implicated in EDS. New EDS variants indicate that besides the collagens, genetic defects affecting the other extracellular matrix (ECM) components and processes as diverse as signaling pathways or intracellular trafficking can contribute to EDS pathogenesis.1,3  

The classification of EDS in 2017 recognizes 13 subtypes with identified mutations in 20 genes. This has replaced the older Villefranche Classification. By far, EDS hypermobile type (hEDS) is the most common type with unknown molecular cause.2,4 2017 international classification of EDSs4

Ehlers-Danlos-Syndrome-Table

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Presentation differs widely among the 13 distinct types of EDS. The hypermobile, classic and vascular subtype of EDS are most common.1,2 Hypermobile EDS (EDS-HT) may impact multiple body systems, including widespread chronic pain, autonomic dysfunction, mast cell activation syndrome (MCAS), psychological disorders and gastrointestinal dysfunction.2 The Classical type may present with congenital dislocation of the hips in newborns, clubfoot, and spondylolisthesis, with joint dislocations later in life, secondary to joint hypermobility. Skin hyperextensibility is one of the most typical features; however, increased bruising and fragility of the skin with gaping wounds from minor trauma are more prevalent.1,2 The skin in Vascular EDS is only mildly hyperextensible but may be thin, pale, and nearly translucent with visible veins.2,5,6 More than 80% of patients with Vascular EDS experience a significant medical problem by age 40, including rupture of the blood vessels and bowel, making it the only form of EDS with a shortened life expectancy.5 Kyphoscoliosis EDS is characterized by newborns hypotonia, fragility of the ocular globe and severe scoliosis.2,3

Arthrochalasia EDS is characterized by congenital bilateral hip dislocation, severe generalized joint hypermobility with recurrent joint dislocations and subluxations, hyperextensible and/or fragile skin and muscle hypotonia. 7 Brittle cornea syndrome most commonly presents with thinning of the cornea with or without rupture and scarring of the cornea. Dermatosparaxis EDS presents with extreme skin fragility with congenital or postnatal skin tears. Spondylodysplastic EDS is characteristic for short stature and muscle hypotonia. Musculocontractural EDS has multiple congenital joint contracture, characteristically adduction-flexion contractures and/or talipes equinovarus. Myopathic EDS presents with congenital muscle hypotonia and/or muscle atrophy that improves with age. Severe and intractable periodontitis of early onset is characteristic for periodontal EDS.4

Specific secondary or associated conditions and complications

Musculoskeletal complications include hyperlaxity of joints, subsequent dislocations and effusions, osteoarthritis, and limb pain.2,8 Neuromuscular impairments include primary muscle hypotonia, fatigue, muscle weakness, myalgia, easy fatigability, decreased strength, and poor proprioception.2,9,10 Gastrointestinal manifestations include constipation, gastroesophageal reflux, diverticulosis, hiatal hernia, umbilical hernia, malabsorption, and esophagitis. Peripheral neuropathy, plexopathy, epilepsy, headache, spontaneous intracranial hypotension, postural hypotension and cerebrovascular disorders are possible neurologic complications.2,7 Cardiac manifestations include mitral valve prolapse, tricuspid valve prolapse, arterial rupture, aortic root dilation or aneurysm, or dissection.2,4 Respiratory complications because of kyphoscoliosis can also occur.2,3 Dental abnormalities can occur, including early-onset periodontitis, mucosal ulceration, congenital absence of teeth, or supernumerary teeth.2 A crossover syndrome between EDS and osteogenesis imperfecta exists due to pathogenic variants in genes COL1A1 or COL1A2, which presents with joint hyperlaxity, early progressive scoliosis, fractures, osteoporosis, short stature, and blue sclerae.2,3,11 A correlation also exists between EDS and Chiari I malformation.2,4

Essentials of Assessment

History

The physician should inquire about skin hyperextensibility, bruising, joint hypermobility and subluxation (frequent ankle sprains or knee buckling), tendon rupture, abnormal wound healing, surgery complications, fatigue, or musculoskeletal pain in the patient and family members. Common sources of pain include weight bearing joints.12 Questions should include the following systems and conditions: gastrointestinal (bleeding, hernias, or rectal prolapse, constipation), cardiovascular (palpitations, syncope, family history of sudden death, or aneurysm), genitourinary (bladder diverticula, hydronephrosis, or polycystic kidney, uterus prolapse or cervical insufficiency), neurological (neuropathic pain due to polyneuropathy or headache due to atlantoaxial instability and craniocervical instability), immunological (MCAS: flushing, cholinergic urticaria, angioedema, hypotension, diarrhea, and rhinitis),  venous (varicose veins), respiratory systems (spontaneous pneumothorax or pulmonary hypertension).2,13 and psychological (anxiety, sleep disorder).2,12

Physical examination

Assessment is crucial and include the following: malformed teeth, bleeding gums, and gingivitis; signs of aortic and/or mitral valve insufficiency; pulmonary hypertension; rectal prolapse; hernias; varicose veins; skin findings of hyperextensibility, easy bruising, thin body habitus, hyperpigmentation, molluscoid pseudotumors (fleshy, heaped-up lesions associated with scars over pressure points, e.g., the elbows and knees), and subcutaneous spheroids (small, hard, freely mobile cyst-like nodules with an outer calcified layer over the bony prominences of the extremities); scoliosis and hyperlordosis; joint instability and hypermobility; and gait evaluation.2,12,13 Hypotonia and motor development should be evaluated for in infants and children.

The Beighton hypermobility criteria to assess joint hypermobility: score 1 point for each of the following

  • Ability to bend and place hands flat on the floor without bending knees;
  • Hyperextension of each knee beyond 10°;
  • Hyperextension of each elbow beyond 10°;
  • Each thumb passive extension to touch the forearm;
  • Each fifth digit passive extension beyond 90°.

A score of 5 or higher is suggestive of joint hypermobility syndrome.5,13

Higher scores on the Beighton scale represent more affected joints rather than a higher degree of laxity.12 In individuals with acquired joint limitations (past surgery, wheelchair, amputations, etc.) affecting the Beighton score calculation, the assessment of generalized joint hypermobility (GJH) may include historical information using the five-point questionnaire (5PQ). If the Beighton score is 1 point below the age and sex specific cut-off AND the at least two positive items in the 5PQ, then a diagnosis of GJH can be made.2

The Five-Point Questionnaire:

  1. Can you now (or could you ever) place your hands flat on the floor without bending your knees?
  2. Can you now (or could you ever) bend your thumb to touch your forearm?
  3. As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?
  4. As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?
  5. Do you consider yourself “double-jointed”?
    A “yes” answer to two or more questions suggests joint hypermobility with 80–85% sensitivity and 80–90% specificity

Functional assessment

Clinical assessment of gait is important, as the hypermobile type (EDS-HT) is associated with slower-than-normal gait with shorter stride length, balance impairments, and increased fall frequency.2, 14 EDS-HT has also been shown to have an association with weakness of lower extremity muscles, poor muscle strength endurance, and reduced functional performance as evaluated by the chair rise test and Arthritis Impact Measurement Scales (AIMS).15Although the syndrome may affect physical function, cognition should not be affected.

Laboratory studies

While the diagnosis of EDS is based on clinical symptoms and family history, it may be beneficial to identify the mutation through collagen protein analysis via skin biopsy or molecular analysis of deoxyribonucleic acid extracted from cultured fibroblasts.2,3,4 Identifying the responsible gene may be useful in testing other family members and for genetic counseling.

Evaluation of clotting factors is recommended if the patient exhibits severe easy bruising.3

Imaging

Imaging is not necessary for the diagnosis of EDS but may be helpful in evaluating for complications associated with the syndrome, such as visceral and orthopedic abnormalities.5 Radiographs may demonstrate calcification of subcutaneous spheroids. A baseline echocardiogram with an aortic diameter measurement is recommended for those younger than 10 years of age. Abnormalities, such as aortic dilatation or mitral valve prolapse, require annual monitoring with an echocardiogram. If the study is normal in an adult, no further echocardiograms are necessary.3 Central nervous system imaging may be helpful in some cases, such as when cerebrovascular complications are suspected or to evaluate for potential Chiari malformation. Abdominal imaging may be warranted if there is concern for aortic pathology. Cardiac, thoracic, and abdominal imaging is recommended prior to competitive sports clearance.

Supplemental assessment tools

Electrodiagnostic studies may be helpful if there is concern for a peripheral neuropathy (e.g., brachial plexus palsy or lumbosacral plexopathy) secondary to increased ligament laxity/stretchability and mechanic trauma.16

Early predictions of outcomes

Early prediction of outcomes is difficult, because there is significant variability in severity even among family members. Nevertheless, vascular EDS is associated with shortened life expectancy because of risks for arterial rupture, aneurysm, or dissection; gastrointestinal perforation or rupture; and uterine rupture during pregnancy.5

Environmental

Environmental factors that could lead to skin trauma or trauma to other organ systems should be assessed.3

Social role and social support system

Patients’ daily functional performance is not entirely due to the extent of the disease, but it is also affected by psychosocial factors.15 Patients, as well as their caregivers and other family members, should be questioned as to how they are adjusting to the disability and with coping with chronic pain. Inquiries should be made into whether they would be receptive to support groups or psychologic services. Patients can be directed to resources, such as the Ehlers-Danlos National Foundation website (http://www.ednf.org/).

Professional issues

Genetic counseling may be helpful to those who have been diagnosed or who are a known carrier. Counseling should also be performed in women of childbearing age, because pregnancy can be problematic in patients with EDS. Infertility and spontaneous abortions have been reported in EDS-HT. 2 Complications can include breech presentation leading to congenital dislocation of the hips or shoulder, extension of episiotomy incisions, tearing of the perineal skin, and uterine/bladder prolapse after delivery. Premature rupture of the membranes occurs more often if the fetus is affected.3

Rehabilitation Management and Treatments

Available or current treatment guidelines

There are no evidence-based treatment guidelines for EDS.

At different disease stages

There are no consistent disease stages, and treatment recommendations are based on the severity and symptoms of the individual patient.

Pain is a common complaint in in as high as 90% patients with EDS. Pain may be limited to musculoskeletal system or widespread and might be acute or chronic.17 The widespread pain often has a strong myofascial component with central sensitization, such as fibromyalgia. 18  Musculoskeletal pain is hypothesized to develop due to mechanical overload during activity and a high risk of repetitive trauma thus pain provoked by activity is a prominent feature of EDS-HT.19 While the optimal rehabilitation program has not been identified, research supports that posture, proprioception, core stability, strength, endurance and motor control, in addition to education, physical activity, and fitness are important components.20 Conservative management is the mainstay of pain management due to poor wound healing in EDS. Treatment includes physical/ occupational therapy, transcutaneous electrical nerve stimulation units, trigger point injections, low-dose naltrexone, and laser therapy.  The use of novel cognitive behavioral therapy (CBT) for EDS patients can be helpful in managing psychological comorbidities due to pain.18 Also, it was demonstrated that physical therapy remains underutilized in EDS patients.21 In a retrospective study, comparing effects of the currently available treatment options for pain and symptom relief, occupational therapy and bracing were reported as the most effective option with 70% of EDS patients reporting improvement.22

Females are more likely to seek medical care for pain and major joint complications. This bias may result from gender differences with respect to pain perception and inherent joint stability, as well as the effects of sex hormones.2

Studies in women indicate that knee ligament laxity and ACL injury occur more frequently during preovulatory and ovulatory phase of the menstrual cycle, when estrogen exceeds progesterone. Hormonal contraceptives have been found to have a possible protective role in ACL tears.2

Children with EDS may present with hypotonia (or hypermobility construed as hypotonia) and developmental delay. The need for a physical and/or occupational therapy program should be assessed by a physician at an early age, because these patients may benefit from early intervention services or school accommodation.

Long-term management of EDS includes special attention to skin care, strategies to preserve joints, maintain balance and manage pain, as well as multisystem clinical monitoring.

Improved joint stability may be achieved by low-resistance exercise such as walking, bicycling and low-impact aerobics to increase muscle tone as opposed to muscle strength. Non-weight-bearing exercises, such as swimming or cycling, may be beneficial in promoting strength and balance. High impact sports and excessive weightlifting should be avoided, because these activities may produce undue strain on hypermobile joints.3 Proprioceptive and strengthening exercises may help prevent injury. Pedorthoses for proper foot alignment may be considered and was found be helpful in relieving adult foot pain and fatigue.23 Wide grip writing utensils can reduce strain and pain on finger joints, and finger orthosis has been demonstrated to be helpful for hand function.24

Coordination of care

An interdisciplinary approach is recommended. The team should include physiatrists, orthopedic surgeons, cardiologists, gastroenterologists, dentists, and other specialists, as necessary, as well as nurses, wound care specialists, social workers, psychologists, and physical and occupational therapists.

Patient & family education

Education should be provided about the significant variability in severity among family members. Protection of skin and joints throughout life should be emphasized. Children should be asked if they pull on their skin in an effort to show off, and this activity should be discouraged. Protective gear, such as pads or bandages over the forehead, knees, and shins should be worn by affected children from an early age. Patients with excessive bruising should refrain from contact sports or heavy exercise.3 Any competitive athletic activity is contraindicated in patients with Vascular EDS.4 Referral to support group services should be offered.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

EDS has wide phenotypic variability, even among family members.

A lack of family history may be due to failure to recognize the disorder, particularly in mildly affected family members.

Degenerative joint disease occurs at a younger age. Chronic pain and impaired balance are common in patients with EDS.

Surgical intervention should be undertaken with caution because of poor wound healing and risk for increased bleeding.

Cutting Edge/Emerging and Unique Concepts and Practice

N/A

Gaps in the Evidence-Based Knowledge

There is a lack of well-designed large studies evaluating the true prevalence and natural history.

The knowledge of the underlying biology of EDS is limited regarding genetic pathways that contribute to disease etiology and pathogenesis.

There is no consensus on cardiac surveillance.

There are no prospective studies evaluating the optimal strategies to promote joint protection, minimize pain, and improve function.

No consensus on the rehabilitation protocol for patients with EDS

References

  1. De Paepe A, Malfait F. The Ehlers Danlos syndrome, a disorder with many faces. Clinical Genetics 2012;82: 1–11.
  2. Gensemer C, Burks R, Kautz S, Judge DP, Lavallee M, Norris RA. Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes. Dev Dyn. 2021 Mar;250(3):318-344. 
  3. Malfait, F.; Castori, M.; Francomano, C.A., et al. The Ehlers-Danlos syndromes. Nat. Rev. Dis. Prim. 2020, 6, 64..
  4. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26.
  5. Watanabe A, Shimada T. Vascular type of Ehlers-Danlos syndrome. J Nippon Med Sch. 2008;75:254-261.
  6. Shabani M, Abdollahi A, Brar BK, et al. Vascular aneurysms in Ehlers-Danlos syndrome subtypes: A systematic review. Clin Genet. 2023 Mar;103(3):261-267. 
  7. Martín-Martín M, Cortés-Martín J, Tovar-Gálvez MI, et al.  Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review. Int J Environ Res Public Health. 2022 Feb 7;19(3):1870.
  8. Voermans NC, Knoop H, Bleijenberg G, van Engelen BG. Pain in Ehlers-Danlos syndrome is common, severe, and associated with functional impairment. J Pain Symptom Manage. 2010;40:370-378.
  9. Voermans NC, Knoop H, van de Kamp N, Hamel BC, Bleijenberg G, van Engelen BG. Fatigue is a frequent and clinically relevant problem in Ehlers-Danlos syndrome. Semin Arthritis Rheum. 2010;40:267-274.
  10. Basem JI, Lin T, Mehta ND. A Comprehensive Review: Chronic Pain Sequelae in the Presence of Ehlers-Danlos Syndrome. Curr Pain Headache Rep. 2022 Dec;26(12):871-876. .
  11. Morlino S, Micale L, Ritelli M, et al. COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers-Danlos syndrome overlap. Clin Genet. 2020;97(3):396-406.
  12. Atwell K, Michael W, Dubey J, et al. Diagnosis and Management of Hypermobility Spectrum Disorders in Primary Care. J Am Board Fam Med. 2021;34(4):838-848.
  13. Castori M, Voermans NC. Neurological manifestations of Ehlers-Danlos syndromes: A review. Iran J Neurol. 2014 Oct 6; 13(4): 190-208.
  14. Rombaut L, Malfait F, De Wandele I, et al. Balance, gait, falls, and fear of falling in women with the hypermobility type of Ehlers-Danlos syndrome. Arthritis Care Res (Hoboken). 2011;63:1432-1439.
  15. Scheper MC, de Vries JE, Verbunt J, et al. Chronic pain in hypermobility syndrome and Ehlers–Danlos syndrome (hypermobility type): it is a challenge. J Pain Res.2015;8: 591-601.
  16. Galan E, Kousseff BG. Peripheral neuropathy in Ehlers Danlos Syndrome. Pediatr Neurol. 1995;12:242-245.
  17. Chopra P, Tinkle B, Hamonet C, et al. Pain management in the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet. 2017;175:212-219.
  18. Basem JI, Lin T, Mehta ND. A Comprehensive Review: Chronic Pain Sequelae in the Presence of Ehlers-Danlos Syndrome. Curr Pain Headache Rep. 2022 Dec;26(12):871-876. 
  19. Engelbert RH, Juul-Kristensen B, Pacey V, et al. The evidence-based rationale for physical therapy treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome. Am J  Med Genet C Semin Med Genet. 2017;175:158-167.
  20. Peterson B, Coda A, Pacey V, et al. Physical and mechanical therapies for lower limb symptoms in children with hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome: a systematic review. J Foot Ankle Res. 2018;11:59.
  21. Feldman ECH, Hivick DP, Slepian PM, et al. Pain symptomatology and management in pediatric Ehlers-Danlos syndrome: a review. Children (Basel). 2020;7:146.
  22. Song B, Yeh P, Nguyen D, et al. Ehlers-Danlos syndrome: an analysis of the current treatment options. Pain Physician 2020;23:429-438.
  23. Reina-Bueno M, Vazquez-Bautista C, Palomo-Toucedo IC et al. Custom-made foot orthosis reduce pain and fatigue in patients with Ehlers-Danlos syndrome. A pilot study. Int J Environ Res Public Health. 2020;17:1359.
  24. Jensen AM, Andersen JQ, Quisth L, et al. Finger orthosis for management of joint hypermobility disorders: relative effects on hand function and cognitive load. Prosthet Orthot Int. 2020. Online a head of print.

Original Version of the Topic

Marykatharine Nutini, DO. Ehlers-Danlos Syndrome. 1/24/2013

Previous Revision(s) of the Topic

Yuxi Chen, MD, Louis Dizon, MD, Atira Kaplan, MD. Ehlers-Danlos Syndrome. 8/18/2016

Yuxi Chen, MD, Jinpu Li, MD, Ayce Atalay, MD. Ehlers-Danlos Syndrome. 9/23/2021

Author Disclosures

Yuxi Chen, MD
Ipsen, Research fund, Principal investigator

Emilee Bell, DO
Nothing to Disclose

Jessi Yu, MD
Nothing to Disclose