Ehlers-Danlos Syndrome

Overview

Definition

Ehlers-Danlos syndrome (EDS) is a group of 13 inherited connective tissue disorders of collagen processing or synthesis. The syndrome is clinically heterogeneous and can affect the skin, joints, blood vessels, and other tissues and is characterized by the following:

• Joint hypermobility
• Cutaneous hyperextensibility/fragility
• Connective tissue hyperextensibility/fragility
• Delayed wound healing/scarring

Epidemiology

• The combined prevalence of all types is reported to be 1 case per 5000 people.
• The classical and hypermobility subtypes of EDS account for the majority of cases.
• 50% of patients have an affected parent.
• Caucasians more commonly affected than other races
• Women = men
• Dermatosparaxis type more common in Ashkenazi Jews

Etiology and pathophysiology

• Connective tissue disorder involving genetic defects in the collagens (a family of proteins)
• Skin collagen alterations found in the reticular dermis: 
  • Irregularities in fibril diameter
  • Irregular collagen shapes
• Multiple gene mutations have been found in association with EDS.
• The genetic basis is known for the majority of EDS types.
• EDS can be inherited as a dominant or recessive genetic condition.

Classification

This list of classifications is not exhaustive; it includes the most common, clinically significant subtypes.

• Classical type (cEDS): 
  • Autosomal dominant inheritance
  • COL5A1 and COL5A2 genes mutated
  • Type I collagen fibrils affected
• Classical-like (clEDS): 
  • Autosomal recessive inheritance
  • TNXB gene mutated
  • → Tenascin X deficiency
  • Integrity of the scaffold in which the collagen lays down affected
• Hypermobility type (hEDS): 
  • Autosomal dominant inheritance
  • Unknown gene mutation
  •  Integrity of the scaffold in which the collagen lays down affected
• Cardiac valvular type (cvEDS):  
  • Autosomal recessive inheritance
  •  COL1A2 gene mutation
  • Type I collagen fibrils affected
• Vascular type (vEDS): 
  • Autosomal dominant inheritance
  • COL3A1 gene mutation
  • Type III procollagen affected

Clinical Presentation

History

• Family history:
  • Autosomal dominant inheritance pattern
  • Autosomal recessive inheritance pattern
• Initial presenting symptoms:
  • Joint symptoms (most commonly dislocation)
  • Skin symptoms

Exam findings

Skin:

• Hyperextensible skin:
  • Defined as skin stretch ≥ 4 cm at a neutral site (neck or ventral aspect of forearm) until resistance is felt
  • Hyperextensible skin observed in:
    • cEDS
    • clEDS
    • Kyphoscoliotic EDS
  • Present in children, but incidence increases with age
• Extensive/abnormal scarring observed in:
  • clEDS 
  • Kyphoscoliotic EDS
• Tendency to bruise easily and heal slowly
• Abnormal/hypertrophic scarring
• Thin/translucent skin

Musculoskeletal:

• Joint hypermobility:
  • Joint dislocations/subluxations are common in most forms of EDS.
  • Often self-reduced by the patient or resolve spontaneously
  • Most common sites of subluxation/dislocation:
    • Shoulder
    • Patella
    • Temporomandibular joint
• Skeletal abnormalities: 
  • Pectus excavatum
  • Kyphoscoliosis
  • Pes planus
  • High-arched palate
• Skeletal/joint abnormality complications:
  • Recurrent subluxations/dislocations
  • Early degenerative arthritis
  • Complex regional pain syndrome
• Muscular hypotonia

Cardiovascular:

• vEDS (and in some rarer types of EDS): 
  • Aneurysms/pseudoaneurysms
  • Dilation of the aortic root
  • Arterial dissection/rupture 
• Heart valve defects (particularly mitral valve prolapse)

Pulmonary:

• Spontaneous pneumothorax
• Emphysema-like physiology

GI:

• Propensity for development of:
  • Hernias
  • Fistulas
  • Diverticula
• Spontaneous rupture of hollow organs
• Dysmotility

Ophthalmic:

• Blue sclerae
• Scleral/corneal rupture with mild trauma
• Retinal detachment
• Myopia

Obstetric/gynecologic:

• Pelvic floor weakness:
  • Vaginal prolapse
  • Uterine prolapse
  • Rectal prolapse
• Uterine fragility:
  • Spontaneous uterine rupture
  • High-risk pregnancy

Miscellaneous:

• Mental development is normal.
• Dental/gingival abnormalities

Diagnosis

Ehlers-Danlos syndrome is generally diagnosed on the basis of patient history and clinical findings.

• Initial evaluation:
  • Major and minor diagnostic criteria exist for each EDS subtype. 
  • Beighton Hypermobility Scale:
    • Set of maneuvers used to detect evidence of joint hypermobility
    • Scoring system most often used in epidemiologic research 
    • A score ≥ 5 of the maximum of 9 points is used to define hypermobility in criteria for EDS.
  • Skin hyperextensibility can be examined by carefully pulling up the skin at a neutral site until the point of resistance.
  • Baseline echocardiography to rule out aortic dilatation
• Genetic testing for the identification of EDS subtype
• Consider clotting studies to rule out hypocoagulable state as cause of bruising.

Management and Prognosis

Management

• No specific cure
• Patient education is key:
  • Prevention/early recognition of complications 
  • Proper screening for complications based on subtype
  • Prenatal planning
• Consider referral:
  • Geneticist 
  • Ophthalmologist
  • Cardiologist
  • Pain specialist
  • Orthopedist
  • Rheumatologist
  • Dermatologist
  • Obstetrician/gynecologist
  • Psychiatrist/behavioral health
• Ascorbic acid (vitamin C) supplementation: 
  • Critical cofactor for collagen fibril synthesis
  • May aid in healing/prevention of scarring
• Vitamin D supplementation to maintain bone density
• Avoid/limit:
  • Contact sports
  • High-impact sports
  • Heavy lifting
• Low-impact muscle-strengthening program
• Appropriate use of bracing/assistive devices
• Obstetric planning/counseling 
• Support group for EDS

Prognosis

• Prognosis varies depending on subtype.
• Generally, the mortality of patients with the classical and hypermobility subtypes is not impacted by the disease.
• The vascular and kyphoscoliotic subtypes have a higher risk of complications that shorten life expectancy.

Clinical Relevance

Differential diagnosis

• Marfan syndrome: autosomal dominant connective tissue disorder that affects the microfibrils and elastin in connective tissue and also presents with joint hypermobility. Marfan syndrome can be distinguished clinically (tall stature, long limbs) and confirmed by genetic testing. Monitoring for cardiovascular complications (aortic dissection, valvular heart disease) is the keystone of management, as these are the main causes of mortality.
• Loeys-Dietz syndrome: autosomal dominant connective tissue disorder characterized by tortuosity of arterial vessels, widely spaced eyes (hypertelorism), a wide/split posterior of the soft palate of the mouth, and aortic aneurysms. The condition is diagnosed clinically and confirmed by genetic testing. Management is centered around the prevention of vascular complications.

Related conditions

• Cutis laxa (elastolysis): rare, inherited, or acquired connective tissue disorder in which the skin becomes inelastic and hangs loosely in folds.
• Pseudoxanthoma elasticum: rare genetic disorder characterized by elastorrhexis (progressive calcification and fragmentation of elastic fibers) that predominantly affects the skin, cardiovascular system, and retina.
• Osteogenesis imperfecta (OI) type I: genetic disorder characterized by bones that break easily, muscle weakness, joint laxity, scoliosis, brittle teeth, and hearing loss.
• Child abuse: Ehlers-Danlos syndrome may resemble child abuse in some patients, a potential medicolegal concern and challenge.