Ehlers-Danlos Syndrome

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Original Editors - Corey Vogt from Bellarmine University's Pathophysiology of Complex Patient Problems project.

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Definition/Description

Ehlers-Danlos syndrome is a hereditary collagen disorder characterized by articular hypermobility, dermal hyperelasticity, and widespread tissue fragility (The Merck Manual).  Individuals with EDS demonstrate defects in the body's connective tissues, manifesting as altered strength, elasticity, integrity, and healing properties of the tissues.  The severity of the syndrome varies greatly depending upon the specific mutation with each type demonstrating integumentary and/or joint hypermobility or laxity.

Ehlers Danlos Syndrome has been reported with an initial discover date and description dating back to the fourth century BC.  The first clinical description of EDS is credited to Tschernogobow in 1892.  However, the name and recognition of the syndrome is credited to Edward Ehlers, a Danish dermatologist, and Henri-Alexandre Danlos, a French physician, who wrote separate reports in 1901 and 1908 respectively.  The two physicians were able to collaborate in providing a description of the pertinent features of the condition as well as accurately identify the associated phenotypes.

In 1997-1998, six discernable phenotypes for EDS were identified (classic, hypermobility, vascular, kyphoscoliosis, arthorchalasia, and dermatosparaxis) by Beighton et. al.  These identifiable forms of EDS are currently recognized by the medical advisory board of the Ehlers-Danlos National Foundation and used in the clinical setting for proper diagnosis. 

Prevalence

Combined prevalence of all subtypes of EDS is about 1 per 5,000.  Hypermobility and classic subtypes are the most common with a prevalence of 1 per 10,000-15,000 and 1 per 20,000-40,000 respectively.  EDS demonstrates equal prevalence amongst males and females of all racial and ethnic backgrounds (Ehlers Danlos National Foundation, Steiner RD - emedicine, Levy HP - Gene Reviews, U.S. National Library of Medicine).

Characteristics/Clinical Presentation

Ehler-Danlos Syndrome contains at least six discernible phenotypes that are individually recognized, but each type contains characteristics similar to the others, which creates difficulty in accurate diagnosis.  Despite the frequent overlap of associated signs and symptoms of the various subtypes of EDS, each specific type presents with the same general clinical characteristics that are a result of faulty or reduced amounts of Type III collagen in the body:  

• Hyperextensible (stretchy) skin
• Tissue fragility
• Poor wound healing resulting in elongated scarring (cigarette paper scars)
• Joint hypermobility
• Increased propensity for joint subluxations/disclocations
• Muscle weakness
• Delayed motor development
• Easy bruising
  

In 1997-1998, Beighton et al. in collaboration with the Ehlers-Danlos National Foundation proposed a system to distinguish the clinical manifestations of EDS into six distinct subtypes.  This nosology is still being used in the clinical setting for proper diagnosis of EDS.

Type	Inheritance	Previous Nomenclature	Major Features	Minor Features	Laboratory
Classic	AD	Type I/II	Skin hyperextensibility,wide atrophic scars, joint hypermobility	smooth velvety skin, easy ; brusing;molluscoid pseudotumors; subcutaneous spheroids; joint hypermobility complications (sprains, subluxations, dislocations); muscle hypotonia; delayed gross motor development; tissue extensibility and fragility complications (hiatal hernia, anal prolapse, cervical insufficiency); postoperative hernia	Abnormalities in skin collagen under electron microscopy; abnormal type V collagen - 30% due to mutation in tenascin
Hypermobility	AD	Type III
Vascular	AD	Type IV
Kyphoscoliosis	AR	Type VI
Arthrochalasia	AD	Type VII A/B
Dermatosparaxis	AR	Type VII C

  Table 2
Diagnostic criteria for Ehlers-Danlos Syndromes – Beighton[9].

Type and Inheritance
Major features
Minor features
Laboratory

---

Classical
AD
Skin hyperextensibility
Widened atrophic scars
Joint hypermobility
Smooth velvety skin
Molluscoid pseudotumors
Subcutaneous spheroids
Complications of joint hypermobility
(sprains, subluxations/dislocations, pes planus)
Muscle hypotonia
Delayed gross motor development
Easy bruising
Manifestations of tissue extensibility and fragility†
Postoperative hernia
Positive family history
Abnormalities in skin collagen under electron microscopy
Abnormal collagen type V
30% due to mutation in tenascin

---

Hypermobility
AD
Skin involvement
(hyperextensibility and/or smooth, velvety skin)
Generalised joint hypermobility
Recurring joint dislocations
Chronic joint/limb pain
Positive family history

---

Vascular
AD
Thin, translucent skin
Arterial/intestinal/uterine fragility or rupture
Extensive bruising
Characteristic facial appearance
Acrogeria
Hypermobility of small joints
Tendon and muscle rupture
Talipes equinovarus
Early onset varicose veins
Arteriovenous, carotid-cavernous sinus fistula
Pneumothorax/pneumohaemothorax
Gingival recession
Positive family history
Sudden death in close relatives
Abnormal type 3 collagen
COL3A1 mutation

---

Kyphoscoliotic
AR
Generalised joint laxity
Severe muscle hypotonia at birth
Scoliosis at birth, progressive
Scleral fragility and rupture of the ocular globe
Tissue fragility, including atrophic scars
Easy bruising
Arterial rupture
Marfan-like habitus
Microcornea
Radiologically considerable osteopenia
Family history
Urinalysis for lysylpyridinoline and hydroxylysylpyridinoline

---

Arthrochalasia
AD
Severe generalised joint hypermobility with recurrent subluxations
Congenital hip dislocation
Skin hyperextensibility
Tissue fragility, including atrophic scars
Easy bruising
Muscle hypotonia
Kyphoscoliosis
Radiologically mild osteopenia
Skin biopsy and demonstration of abnormal collagen type 1

---

Dermatosparaxis
AR
Severe skin fragility
Sagging, redundant skin
Soft doughy skin texture
Easy bruising
Premature rupture of fetal membranes
Large hernias (inguinal and umbilical)
Demonstration of abnormal collagen 1 chains in skin 
 

Associated Co-morbidities

Many different medical conditions/disease states occur in individuals with EDS.  Examples of co-morbidities include:

• Gastroesophageal reflux
• Gastritis
• Irritable Bowel Sydrome
• Autonomic Dysfunction (neurally mediated hypotension, postural orthostatic tachycardia syndrome, paroxysmal supraventricular tachycardia)
• Aortic root dilatation
• Mitral valve prolapse

Medications

Analgesics

• Acetaminophen
• Tramadol
• Lidocaine
• Tricyclic antidepressants
• Opioids

NSAIDS (ibuprofen, naproxen, etc)

• Ibuprofen, naproxen, etc
• Cox-2 Inhibitors

Muscle relaxants

Glucosamine and Chondroitin

Diagnostic Tests/Lab Tests/Lab Values

Clinical Examination and a detailed family history have proven to be the most effective means of accurately diagnosing EDS

Laboratory studies can be utilized as supporting evidence to confirm the diagnosis of specific subtypes of EDS. 

Biochemical Studies can be used to analyze the make-up of collagen molecules in cultured skin fibroblasts and detect alterations to support a diagnosis of EDS:

• Type IV EDS - Vascular
• Type VIIA and VIIB EDS- Arthrochalasia
• Type VIIC - Dermatosparaxis

Molecular testing utilizing DNA analysis can be used in diagnosis of EDS:

• Type IV - Vascular
• Type VII - Arthrochalasia/Dermatosparaxis

Urinary Analyte Assay can be used in diagnosis of EDS:

• Type VI - Kyphoscoliotic

CT scanning, MRI scanning, ultrasonography, and angiography are useful in diagnosing Type IV (Vascular) EDS with reports suggesting the presence of arterial aneurysms, arterial dissections, arterial ectasias, and arterial occlusions.

Ultrastructural examination of collagen fibrils has been utilized as an assistive tool for diagnosis of Type I/II (Classical) EDS and Type VIIA/Type VIIB ( Arthrochalasia) EDS.

Skin Biopsy using histopathologic analysis has yet to be proven as beneficial in the diagnostic process of EDS.

Causes

EDS is classified as an inherited connective tissue disease.  Three patterns of inheritance have been linked with the various subtypes of EDS: autosomal dominant, autosomal recessive, and X-linked, the rarest form.  The exact source of genetic mutation responsible for the disease state is unknown.  However, mutations in ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and TNXB genes have been linked to causation of EDS. 

COL1A1, COL1A2, COL3A1, COL5A1, COL5A2 encode the manufacture of proteins that are responsible for multiple types of collagen

ADAMTS2, PLOD1, and TNXB encode the manufacture of proteins that interact with or process collagen

 

EDS presents with 100% penetrance, but expression varies greatly amongst the many types

Systemic Involvement

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Medical Management (current best evidence)

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Physical Therapy Management (current best evidence)

Resistance training

• low resistance
• high repetitions

Myofascial release

• pain relief
• muscle spasms

Modalties

• hot/cold pack
• massage
• ultrasound
• electrical stimulation
• acupunture
• acupressure

Alternative/Holistic Management (current best evidence)

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Differential Diagnosis

Marfans Syndrome

Loeys-Dietz Syndrome

Stickler Syndrome

Williams Syndrome

Aarskog-Scott Syndrome

Fragile X Syndrome

Achondroplasia/hypochondroplasia

Osteogenesis Imperfecta

Aneuploidies

• Down Syndrome
• Turner Syndrome
• Klinefelter Syndrome

Case Reports

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Resources

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Recent Related Research (from Pubmed)

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References

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