Ehlers-Danlos Syndrome

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Definition/Description

Ehlers-Danlos syndrome is a hereditary collagen disorder characterized by articular hypermobility, dermal hyperelasticity, and widespread tissue fragility.  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. 

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 (atrophic scarring) 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 Positive family history	Abnormalities in skin collagen under electron microscopy Abnormal type V collagen - 30% due to mutation in tenascin
Hypermobility	AD	Type III	Skin involvement (hyperextensibility and/or smooth, velvety skin) Generalized joint hypermobility	Recurring joint dislocations Chronic joint/limb pain Positive family history
Vascular	AD	Type IV	Thin, translucent skin Arterial/intestinal/uterine fragility or rupture Extensive bruising Characteristic facial appearance	Acrogeria Hypermobility of small joints Tendon/muscle rupture Talipes equinovarus Early onset varicose veins Arteriovenous, carotid-cavernous sinus fistula Pneumothorax/pneumohemothorax Gingival recession Positive family history Sudden death in close relatives	Abnormal type III collagen COL3AI mutation
Kyphoscoliosis	AR	Type VI	General joint hypermobility Severe muscle hypotonia at birth Progressive scoliosis present from birth Scleral fragility or rupture of ocular globe	Tissue fragility (atrophic scarring); eary bruising Arterial rupture Marfan-like habitus Microcornea Osteopenia as defined radiologically Positive family history	Urinalysis for lysylpyridinoline and hydroxylysylpyridinoline
Arthrochalasia	AD	Type VII A/B	Severe generalized joint hypermobility Recurrent joint subluxations Congenital bilateral dislocated hips	Skin hyperextensibility Tissue fragility (atrophic scarring) Easy bruising Muscle hypotonia Kyphoscoliosis Mild osteopenia as defined radiologically	Skin biopsy and demonstration of abnormal type I collagen
Dermatosparaxis	AR	Type VII C	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 type I collagen chains in skin

_{AD = Autosomal Dominant
AR = Autosomal Recessive}

                                                                               

 

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
• Periodontal disease (friability, gum disease, gum recession)
• Temporomandibular Joint dysfunction
• Depression

Medications

Analgesics - pain relief 

• Acetaminophen
• Tramadol
• Lidocaine
• Tricyclic antidepressants
• Serotonin/norepinephrine receptor inhibitors
• Opioids

NSAIDS - anti-inflammatory effect

• Ibuprofen, naproxen
• Cox-2 Inhibitors
• Corticosteriod injections (pain and inflammation)

Muscle relaxants - treatment of myofascial spasms

Glucosamine and Chondroitin - treatment of osteoarthritis

Supplemental magnesium/potassium - muscle relaxation and pain relief

Vitamin C - enhancement of wound healing and proliferation of collagen synthesis

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.  

Major diagnostic criteria typically includes:

• Joint hypermobility as indicated by a score of greater than or equal to 5/9 on the Beighton scale
• Soft skin or skin hyperextensibility as defined by >1.5 cm on volar surface of forearm
• Fragile skin or significant skin/soft tissue abnormalities (easy bruising, delayed wound healing, atrophic scarring, easy tendon, ligament, vessel rupture)

Minor diagnostic criteria typically includes:

• Positive family history
• Recurring subluxations/dislocations
• Chronic joint, limb, or back pain
• Altered blood pressure responses (neurally mediated hypotension or postural orthostatic tachycardia)
• Functional bowel disorders
• High, narrow palate
• Dental crowding 

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

Musculoskeletal

• Joint laxity manifesting in recurrent joint subluxations/dislocations due to minimal trauma and/or spontaneous onset.  Joints involved can include joints of the extremities, vertrebral column, costo-vertebral, costo-sternal articulations, and temporomandibular joints
• Osteoarthritis resulting in early onset of degenerative joint disease as a result of increased mechanical stress placed on joints due to extreme ligamentous and articular laxity
• Osteopenia due to reduction in general bone density.  Precursor and predisposition to early onset of osteoporosis due to abnormally low bone density
• Osteoporosis due to reduction in general bone bone density up to 0.9 standard deviations lowering than the average, healthy adult
• Scoliosis
• Kyphosis
• Chronic joint, ligament, tendon muscle pain due to myofascial and/or neuropathic source
• Headaches related to muscle tension in cervical spine and TMJ dysfunction

Neuromuscular

• Low muscle tone
• Generalized muscle weakness

Cardiopulmonary

• Dysautonomia or Autonomic Dysfunction resulting in abnormal chest pain, palpitations at rest or with exertion, or abnormal blood pressure responses.  Conditionn can be manifested as premature atrial complexes, paroxysmal supraventricular tachycardia, neurally mediated hypotension (NMH), or postural orthostatic tachycardia syndrome (POTS).  Occurs in 33-50% of individuals with EDS, especially hypermobility and classic subtypes
• Aortic Root Dilation resulting in predisposition to arterial fragility or rupture.  Typically occurs in a mild form in 25-33% of individuals with hypermobility and classic subtypes of EDS.  Appears to be less severe than found in Marfan's Syndrome displaying no increased risk of dissection unless a prominent dilatation is present.  Places indivdual at increased risk for an abdominal aortic aneurysm (AAA). 
• Mitral Valve Prolapse with increased risk of developing infective endocarditis

Gastrointestinal

• Functional Bowel Disorders (gastritis, irritable bowel syndrome, gastroesophageal reflux) occur in up to 50% of individuals with EDS

Integumentary

• Hyperextensibility of skin
• Fragility of sof tissue resulting in increased likelihood of rupture or tearing of internal organs

Genitourinary

• Uterine Fragility
• Premature rupture of fetal membranes during pregnancy
• Pelvic prolapse
• Dyspareunia

Oral/Dental

• Periodeontal disease resulting in friability, gingivitis, and gum recession
• Presence of a high, narrow palate combined with dental crowding

Hematologic

• Easy bruising
• Prolonged bleeding times, epistaxis, and menometrorrhagia

Psychiatric

• Depression

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

• Characterized by additional skeletal, ocular, cardiovascular, pulmonary, adn integumentary signs and symptoms beyond those characteristic of EDS.  Mimics hypermobility subtype of EDS, but clinical diagnosis is confirmed by presence of mutation in FBN1 gene.

Loeys-Dietz Syndrome

• Characterized by multiple arterial aneurysms and tortuosity.  Other clinical signs and symptoms include ocular hypertelorisma and a bifid uvula.  Mimics vascular subtype of EDS, but clinical diagnosis is confirmed by detection of mutation in TGFBR1 or TGFBR2 gene.

Stickler Syndrome

• Characterized by sensorineural hearing loss, vitreoretinal abnormalities, and cleft palate.  Clinical diagnosis is often based on the presence of clinical features, but the syndrome has been associated with mutations in one of three genes (COL2A1, COL11A1, or COL11A2)

Williams Syndrome

• Characterized by a gene deletion resulting in cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, mental retardation, a specific cognitive profile including personality, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, early puberty).  Clinical diagnosis consists of the presence of a contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that controls the elastin gene.

Aarskog-Scott Syndrome

• Characterized by a shawl scrotum, widow's peak, short upturned nose, other dysmorphic features, and occasionally mental retardation.  Clinical diagnosis consists of presence of a mutation of the FGD1 gene.

Fragile X Syndrome

• Not commonly confused with EDS, but does share some characteristics similar to EDS such as joitn laxity and EDS-like skin abnormalities.  In affected males, characterized by large head, long face, prominent forehead and chin, protruding ears, joint laxity, large testes, and moderate retardation.  In affected females, characterized by mild retardation.  Clinical diagnosis consists of presence of a mutation of the FMR1 gene.

Achondroplasia/hypochondroplasia

• Characterized by short stature with distinguished skeletal features.  Clinical diagnosis consists of characteristic clinical and radiographic findings in 70-99% of affected individuals as well as the presence of a mutation in the FGFR3 gene.

Osteogenesis Imperfecta

• Characterized by the presence of multiple fractures and in some cases, dentinogenesis imperfecta (grey or brown teeth).  Biochemical testing reveals the presence of abnormalities in structure and quantity of type I collagen (98% of type II OI, 90% of type I OI, 84% of type IV OI, 84% of type III OI).  About 90% of individuals with Type I-IV OI present with a mutation in either COL1A1 or COL1A2 genes.

Aneuploidies (Down Syndrome, Turner Syndrome, Klinefelter Syndrome)

• Characterized by easily recognizable dysmorphic features and/or mental retardation with severity dependent upon degree of chromosomal deletions or duplications.

Case Reports

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Resources

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Recent Related Research (from Pubmed)

http://www.ncbi.nlm.nih.gov/pubmed/19955990?tool=MedlinePlus

References

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