Ehler Danlos syndrome

Author(s): Yuxi Chen, MD, Louis Dizon, MD, Atira Kaplan, MD, PGY-3

Originally published:01/24/2013

Last updated:08/18/2016

1. 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.2 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.3

Patho-anatomy/physiology

Genetic defects affecting the biosynthesis and structure of collagen type I, III and V have been implicated in EDS and form the basis of the Villefranche Classification. The classic, hypermobility and vascular subtype of EDS are most common.1,4-6

Type Clinical Findings Inheritance Gene Defect
Classical (I: gravis; II: mitis)* Skin/joint hypermobility, atrophic scars, easy bruising, affects type V collagen production Autosomal Dominant COL5A1, COL5A2
Hypermobility (III: hypermobile)* Joint hypermobility, pain, dislocations Autosomal Dominant Unknown
Vascular (IV: arterial eccchymotic)* Translucent skin with visible veins, arterial/uterine rupture, bruising, small joint hyperextensibility, most severe form Autosomal Dominant COL33A1
Kyphoscoliosis (VI: ocular scoliotic)* Hypotonia, joint laxity, congenital scoliosis, ocular fragility Autosomal Recessive Lysyl-hydroxylase
Arthrochalasia (VIIa: arthrochalasismultiplex congenita; VIIb: arthrochalasismultiplex congenita)* Severe joint hypermobility, scoliosis, bruising Autosomal Dominant COL1A1, COL1A2
Dermatosparaxsis (VIIc: humandermatosparaxis)* Severe skin fragility, cutis laxa, bruising Autosomal Recessive Procollagen N-peptidase

*Corresponding Berlin Classification types are in parentheses.

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

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

Presentation differs widely among the 6 distinct types of EDS. The classic, hypermobility and vascular subtype of EDS are most common.1 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.5,7 Kyphoscoliosis EDS is characterized by fragility of the ocular globe and severe scoliosis.2

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.2,9,10Gastrointestinal manifestations include constipation, gastroesophageal reflux, diverticulosis, hiatal hernia, umbilical hernia, malabsorption, and esophagitis.4 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 kyposcoliosis can also occur.2 Dental abnormalities can occur, including early-onset periodontitis, mucosal ulceration, congenital absence of teeth, or supernumerary teeth.6,11A crossover syndrome between EDS and osteogenesis imperfecta exists, which presents with joint hyperlaxity, early progressive scoliosis, fractures, osteoporosis, short stature, and blue sclerae.2,12 A correlation also exists between EDS and Chiari I malformation.4

2. 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. Questions should include the following systems and conditions: gastrointestinal (bleeding, hernias, or rectal prolapse), cardiovascular (palpitations, syncope, family history of sudden death, or aneurysm), genitourinary (bladder diverticuli, hydronephrosis, or polycystic kidney, uterus prolapse or cervical insufficiency), venous (varicose veins), and respiratory systems (spontaneous pneumothorax or pulmonary hypertension).13,14

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; varicose veins; skin findings of hyperextensibility, easy bruising, thin body habitus, hyperpigmentation, mulluscoid psuedotumors (fleshy, heaped-up lesions associated with scars over pressure points, eg, 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.2,13,14Hypotonia and motor development should be evaluated for in infants and children.13,

The Beighton hypermobility criteria to assess joint hypermobility: score 1 point for each of the following
1. Ability to bend and place hands flat on the floor without bending knees;
2. Hyperextension of each knee beyond 10°;
3. Hyperextension of each elbow beyond 10°;
4. Each thumb passive extension to touch the forearm;
5. Each fifth digit passive extension beyond 90°. A score of 5 or higher is suggestive of joint hypermobility syndrome.5,14

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.15,16 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).17Although 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.2,11 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.2

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.2 Central nervous system imaging may be helpful in some cases, such as when cerebrovascular complications are suspected or to evaluate for potential Chiari malformation.4 Abdominal imaging may be warranted if there is concern for aortic pathology. Cardiac, thoracic, and abdominal imaging is recommended prior to competitive sports clearance.4

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.18

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.5,7

Environmental

Environmental factors that could lead to skin trauma or trauma to other organ systems should be assessed.2

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.17 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. 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.2

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. While the optimal rehabilitation program has not been identified, research supports that posture, proprioception, strength, and motor control, in addition to education, physical activity, and fitness are important components.19Females 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.20

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. These patients may also benefit from 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. Nonweight-bearing exercises, such as swimming or cycling, may be beneficial in promoting strength and balance. High impact sports and excessive weight lifting should be avoided, because these activities may produce undue strain on hypermobile joints.2Proprioceptive and strengthening exercises may help prevent injury. Pedorthoses for proper foot alignment may be considered. Wide-grip writing utensils can reduce strain and pain on finger joints.

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.2 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.

Patients with Vascular EDS, the most severe form, are at risk for rupture of blood vessels or bowel.

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.

Pregnancy may be complicated in patients with EDS.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

NA

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

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

There is little information in the literature on the incidence of pregnancy complications in patients with EDS.

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. Malfait F, Wenstrup RJ, De Paepe A. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med. 2010;12:597-605.
  3. Steinmann B, Royce P, Superti-Furga A. The Ehlers-Danlos syndrome. In: Royce P, Steinmann B, eds. Connective Tissue and Its Heritable Disorders. New York: Wiley-Liss; 2002:431-524.
  4. Schroeder LE, Lavallee ME. Ehlers-Danlos syndrome in athletes. Curr Sports Med Rep. 2006;5:327-334.
  5. Watanabe A, Shimada T. Vascular type of Ehlers-Danlos syndrome. J Nippon Med Sch. 2008;75:254-261.
  6. Abel MD, Carrasco LR. Ehlers-Danlos syndrome: classifications, oral manifestations, and dental considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:582-590.
  7. Savasta S, Merli P, Ruggieri M, Bianchi L, Sparta MV. Ehlers-Danlos syndrome and neurological features: a review. Childs Nerv Syst. 2010;27:365-371.
  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. Voermans NC, van Alfen N, Pillen S, et al. Neuromuscular involvement in various types of Ehlers-Danlos syndrome. Ann Neurol. 2009;65:687-697.
  11. Malfait F, Hakim AJ, De Paepe A, Grahame R. The genetic basis of the joint hypermobility syndromes. Rheumatology. 2006;45:502-507.
  12. Cabral WA, Makareeva E, Colige A, et al. Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. J Biol Chem. 2005;280:19259-19269.
  13. Tachdjian MO. Clinical Pediatric Orthopaedics: The Art of Diagnosis and Principles of Management. Stamford: Appleton & Lange; 1997.
  14. Castori M, Voermans NC. Neurological manifestations of Ehlers-Danlos syndromes: A review. Iran J Neurol. 2014 Oct 6; 13(4): 190-208.
  15. 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.
  16. Levy HP. Ehlers-Danlos Syndrome, Hypermobility Type. Seattle, WA: GeneReviews; 2004.
  17. 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.
  18. Galan E, Kousseff BG. Peripheral neuropathy in Ehlers Danlos Syndrome. Pediatr Neurol. 1995;12:242-245.
  19. Keer R, Simmonds J. Joint protection and physical rehabilitation of the adult with hypermobility syndrome. Curr Opin Rheumatol. 2011;23:131-136.
  20. Castori M, Camerota F, Celletti C, et al. Ehlers-Danlos syndrome hypermobility type and the excess of affected females: possible mechanisms and perspectives. Am J Med Genet A. 2010b;152A:2406–8

Original Version of the Topic:

Marykatharine Nutini, DO. Ehler Danlos Syndrome. Publication Date: 2013/01/24

Author Disclosure

Yuxi Chen, MD
Nothing to Disclose

Louis Dizon, MD
Nothing to Disclose

Atira Kaplan, MD, PGY-3
Nothing to Disclose

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