Ehlers-Danlos Syndrome

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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. The newest classification includes 13 subtypes with autosomal dominant or recessive inheritance pattern, caused by defects in collagens and other related extracellular matrix proteins.^1,2

Clinical features are summarized in the table.^1.2 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 pseudo‐tumours; 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	Early‐onset 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.

A list of managment principles and characteristics^1-7:

Skin:

Usage of 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)

References:

^{1. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):8-26.}

^{2. Malfait F, Castori M, Francomano CA, Giunta C, Kosho T, Byers PH. The Ehlers-Danlos syndromes. Nat Rev Dis Primers. 2020 Jul 30;6(1):64}

^{3.Zhou Z, Rewari A, Shanthanna H. Management of chronic pain in Ehlers-Danlos syndrome: Two case reports and a review of literature. Medicine (Baltimore). 2018 Nov;97(45):e13115.}

^{4. Benrashid E, Ohman JW. Current management of the vascular subtype of Ehlers-Danlos syndrome. Curr Opin Cardiol. 2020 Nov;35(6):603-609.}

^{5. Homere A, Bolia IK, Juhan T, Weber AE, Hatch GF. Surgical Management of Shoulder and Knee Instability in Patients with Ehlers-Danlos Syndrome: Joint Hypermobility Syndrome. Clin Orthop Surg. 2020 Sep;12(3):279-285}

^{6. Levine D, Work B, McDonald S, Harty N, Mabe C, Powell A, Sanford G. Occupational Therapy Interventions for Clients with Ehlers-Danlos Syndrome (EDS) in the Presence of Postural Orthostatic Tachycardia Syndrome (POTS). Occup Ther Health Care. 2021 Sep 14:1-18.}

^{7. Blagowidow N. Obstetrics and gynecology in Ehlers-Danlos syndrome: A brief review and update. Am J Med Genet C Semin Med Genet. 2021 Dec;187(4):593-598.}