BASICS

DESCRIPTION

• Ehlers–Danlos syndrome is a group of connective tissue disorders characterized by joint hypermobility, hyperextensible skin, and fragile connective tissue.

• New classification system describes 6 types:

– Classic type (formerly types I and II, characterized by joint hypermobility, skin laxity and fragility).

– Hypermobility type (formerly type III, characterized by joint hypermobility).

– Vascular type (formerly type IV, complicated by arterial or bowel rupture).

– Kyphoscoliosis type (formerly type VI or ocular-scoliotic type, characterized by globe fragility, scoliosis, and skin and joint laxity).

– Arthrochalasis type (formerly type VIIB, characterized by short stature, joint laxity and dislocations).

– Dermatosparaxis type (formerly type VIIC, characterized by fragile skin with sagging and folding).

– Tenascin-X-deficient type (characterized by joint hypermobility, hyperelastic skin, and fragile tissue).

EPIDEMIOLOGY

Prevalence

• The prevalence of Ehlers–Danlos syndrome is reported to be 1 in 5,000–10,000 individuals. However, the disease may be underdiagnosed due to milder presentations.

– The kyphoscoliosis type affects 2% and is 1 of the less common types.

RISK FACTORS

Genetics

• Varies by type: the kyphoscoliosis and the dermatosparaxis types are autosomal recessive, and the remaining types are autosomal dominant.

• The ADAMTS2, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and TNXB genes are all associated with Ehlers–Danlos.

– These genes are responsible for the assembly and modification of collagen molecules.

GENERAL PREVENTION

Genetic counseling.

PATHOPHYSIOLOGY

Gene mutations result in deficient collagen biosynthesis, primarily of types I and III, leading to fragility of collagen-containing structures.

ETIOLOGY

The various types of Ehlers–Danlos syndrome are due to mutations in many genes coding for collagen synthesis or posttranslational modification.

DIAGNOSIS

HISTORY

• Family history.

• Muscle weakness.

• Joint pain.

• Easy bruising.

• Dental problems.

• Ocular problems.

PHYSICAL EXAM

• Skin usually white, soft, doughy, hyperextensible, fragile, and with visible underlying vessels.

• Flexible fingers and toes.

• Molluscoid pseudotumors—spongy tumors overlying scars

• Cardiac defects.

– Mitral valve prolapse.

– Dysautonomia.

• Abnormal wound healing.

• Increased bleeding (platelet aggregation dysfunction).

• Ocular defects.

– Retinal hemorrhage.

– Retinal detachment (due to stretching of collagenous sclera).

– Keratoconus.

– Lens subluxation.

– Angioid streaks.

– Dry eyes.

– Strabismus.

– Glaucoma.

– Blue sclera.

– Carotid–cavernous sinus fistula.

– Globe rupture.

– Myopia.

– Posterior staphyloma.

– Photophobia.

• Musculoskeletal features.

– Hyperextensible joints.

– Spontaneous dislocation.

– Sprain.

– Subluxation.

– Kyphoscoliosis (convex curving of the spinal column both backwards and sideways).

– Hallus valgus (bunion).

– Pes planus (flat foot).

– Genu recurvatum (hyperextension of knee).

• Functional bowel disorder.

– Gastritis.

– Irritable bowel syndrome.

• Nerve compression (carpal tunnel).

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• No screening laboratory tests.

• Secondary laboratory testing includes the following:

– Collagen typing.

– Collagen gene mutation testing (see “Genetics”).

– Lysyl oxidase or hydroxylase activity.

Imaging

• No initial imaging.

• Secondary imaging may show:

– Calcification of nodules opaque on radiographs.

– Joint dislocation/subluxation.

Diagnostic Procedures/Other

• Echocardiography (mitral valve prolapse).

• Skin biopsy (not sensitive).

Pathological Findings

• Histology reveals whorled, sparse, and disorderly collagen.

• Irregular diameter of fibrils.

DIFFERENTIAL DIAGNOSIS

• Elastolysis.

• Loeys–Dietz syndrome.

• Pseudoxanthoma elasticum.

• Turner syndrome.

• Cartilage-hair hypoplasia syndrome.

• Muscular hypotonia.

TREATMENT

MEDICATION

First Line

• Unsatisfactory medical treatments.

• Treatment is largely supportive.

Second Line

• Vitamin C—cofactor for collagen fibril synthesis.

ADDITIONAL TREATMENT

General Measures

• Care with surgery (vascular rupture and increased bleeding risk).

• Care with anesthesia (cervical spine and airway trauma).

• Avoidance of contact sports (types IV and VI) due to spontaneous vascular rupture.

• Care with pregnancy—reports of premature rupture of membranes.

Issues for Referral

• Ophthalmology.

• Dental.

• Orthopedics.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Ophthalmology.

• Primary care doctor or dermatologist for periodic skin examinations.

• Orthopedics (braces, surgical repair of joints).

• Rehabilitation (physical and occupational therapy).

• Genetic counseling prior to pregnancy.

PATIENT EDUCATION

• The Ehlers–Danlos National Foundation (www.ednf.org).

PROGNOSIS

• Generally patients have a normal lifespan.

• Risk of large vessel or organ rupture with the vascular and kyphoscoliosis types with possible sudden death.

COMPLICATIONS

• Organ rupture (uterus or bowel).

• Vessel rupture (aortic aneurysm).

• Globe rupture.

• Arthritis.

ADDITIONAL READING

• Beighton P. Serious Ophthalmological complications in the Ehlers-Danlos syndrome. Br J Ophthalmol 54(4):263–268.

• Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997. Am J Med Genet 77:31–37.

• Pollack JS, Custer PL, Hart WM, Smith ME, Fitzpatrick MM. Ocular Complications in Ehlers-Danlos Syndrome Type IV. Arch Opthalmol 115:416–419.

CODES

ICD9

• 361.9 Unspecified retinal detachment

• 362.81 Retinal hemorrhage

• 756.83 Ehlers-danlos syndrome

CLINICAL PEARLS

• Ehlers–Danlos is underdiagnosed because of varied presentation.

• The vascular type of Ehlers–Danlos may not present with joint hypermobility or skin hyperelasticity.

• Ehlers–Danlos syndrome is primarily a clinical diagnosis, and most individuals will not likely have any symptoms throughout their lifetime.