The term Ehlers-Danlos syndrome (EDS) encompasses a group of clinically and genetically heterogenous connective tissue disorders that share to varying degrees the clinically manifestations of skin hyperextensibility, joint hypermobility and tissue fragility [1]. The newest classification includes 13 subtypes with autosomal dominant or recessive inheritance pattern, caused by defects in collagens and other related extracellular matrix proteins.

Clinical features are summarized in the table. Further information to common subtypes can be found on the respective pages.

 

 

Ehlers-Danlos subtype

Inheritance

Defective gene(s)

Main clinical features

Classical EDS

AD

COL5A1, COL5A1,

rare: COL1A1 c.934C > T, p.Arg312Cys

Hyperextensible, soft, fragile skin; atrophic scarring; easy bruising; molluscoid pseudotumours;

generalized joint hypermobility;

history of premature birth;

Classical-like EDS

AR

TNXB

Similar to cEDS;

variable muscle weakness/atrophy;

Cardiac-valvular EDS

AR

COL1A2 (biallelic mutations that lead to COL1A2 nonsense-mediated mRNA decay and absence of pro a2(I) collagen chains)

Similar to cEDS;

cardiac valvular abnormalities;

Vascular EDS

AD

COL3A1;

Rare: COL1A1

c.934C > T, p.Arg312Cys c.1720C > T, p.Arg574Cys c.3227C > T, p.Arg1093Cys

Bowel, arterial and uterine rupture at a young age;

Thin, translucent, hyperextensible skin; easy bruising; acrogeria;

small joint hypermobility; talipes equinovarus, congenital hip

dislocation; pneumothorax

Hypermobile EDS

AD

Unknown

Marked generalized joint hypermobility;

Soft, velvety skin; atrophic scarring, unexplained striae;

musculoskeletal pain;

Arthrochalasia EDS

AD

COL1A1, COL1A2

Extreme laxity of joints with dislocations; soft, mild hyperextensible skin;

muscle hypotonia;

Dermatosparaxis EDS

AR

ADAMTS2

Marked fragility of skin; redundant (lax) skin with excessive skin folds; severe bruisability; growth retardation, umbilical herniae, blue sclerae

Kyphoscoliotic EDS

AR

PLOD1, FKBP14

Congenital muscle hypotonia;

(congenital) kyphoscoliosis;

generalized hypermobility with dislocations; hyperextensible skin;

ocular fragility (PLOD1); sensorineural hearing loss (FKBP14)

Brittle Cornea syndrome

AR

ZNF469, PRDM5

Thin cornea with/without rupture; blue sclerae; early onset progressive keratoconus/keratoglobus;

mild skin involvement; small joint hypermobility

Spondylodysplastic EDS

AR

B4GALT7, B3GALT6, SLC39A13

Short stature; muscle hypotonia; bowing of limbs; osteopenia; delayed cognitive development;

Skin and joint involvement similar to cEDS;

Musculocontractural EDS

AR

CHST14, DSE

Congenital multiple contractures; craniofacial abnormalities; skin hyperextensible and fragile skin, easy bruising; gross motor delay; variable cardiac, renal and gastrointestinal involvement

Myopathic EDS

AD or AR

COL12A1

Congenital muscle hypotonia/atrophy; joint contractures; soft, doughy skin;

hypertrophic or atrophic scarring

Periodontal EDS

AD

C1R, C1S

Earlyonset periodontal disease; pretibial plaques; soft, hyperextensible skin; easy bruising; joint hypermobility;

Treatment

The management and treatment of EDS patients should be individualized, based upon the patients’ symptoms, clinical findings and systemic manifestations. For all types, counseling and reviewing the specific features of the subtype as well as educating the patients to facilitate recognition of potentially serious symptoms that may require urgent medical intervention, is essential.

Skin:

  • Protective helmets and pads over knees, shins, elbows, especially during sports (prevent lacerations, trauma) as wounds, cuts and bruises may take longer to heal and may scar poorly
  • Closure of deep and large skin wounds with two layers of stitches (deep and superficial, which should be left in place twice as long as usual)

Joints:

  • Treatment goal includes the prevention of recurrent joint dislocations, chronic musculoskeletal pain and early onset osteoarthritis
  • Orthopaedic or rheumatological evaluation and management
  • Physical therapy and low-resistance exercises (e.g. walking, bicycling, swimming) to increase muscle tone, strengthen large muscle groups and stabilize loose joints
  • Assistive devices, or lightweight orthoses (braces), splints to support unstable joints, assist with walking
  • Evaluation by a pedorthist/podiatrist if feet abnormalities or lower limb pain are present
  • Occupational therapy, especially if upper extremity is significantly involved
  • Avoidance of joint hyperextension and high impact sports (e.g. football, fighting)

Pain:

  • Multidisciplinary management (medication, exercise, psychosocial support)
  • Pharmacologic treatment includes analgesics, selected antidepressants, antiseizure medications, muscle relaxants
  • Opiods and local anesthetics tend to be less effective
  •  

Cardiovascular:

  • Control of blood pressure to reduce the risk for arterial rupture – risk assessment based on subtype
  • Evaluation of medical therapy with celiprolol (long acting beta1 antagonist)
  • Early baseline echocardiogram and follow-up studies timed according to subtype and abnormalities

Other:

  • Medical alert device (indicating diagnosis and possible complications) for patients with vascular EDS to facilitate emergency medical care. Its usage should be also considered for other EDS subtypes that go along with an increased risk for vascular/acute events (e.g. classical EDS, kyphoscoliosis EDS)
  • Psychosocial support
  • Ophthalmologic evaluation (myopia, screening for glaucoma, retinal detachment)
  • Referral to a specialist for orthostasis and symptoms of possible autonomic dysfunction
  • Referral to an expert for gastroenterology (gastrointestinal problems including bowel dysmotility)
  • Referral to an expert in urology/gynecology (bladder dysfunction, intestinal cystitis)
  • Referral to a neurologist/rheumatologist (muscle weakness, myalgia)
  • Referral to a neurosurgeon (symptomatic spinal instability – should be suspected when symptoms (pain, neurologic or autonomic symptoms) worsen if the cervical spine is moved in certain directions)

Pregnancy:

  • Increased risk for miscarriage, premature rupture of membranes, rupture of arteries (especially vascular EDS and kyphoscoliotic EDS)