36: VASCULAR EHLERS-DANLOS SYNDROME

A 23-year-old woman was seen in a vascular surgery clinic for a pulsatile mass over the calf for a few weeks' duration. She recollected sustaining a minor injury while she was horse riding. She also had a history of easy bruisability. Her brother also has similar history of skin bruising with hypermobile joints and thin skin.

Further investigation suggested a pseudoaneurysm arising from the anterior tibial artery (Figure 36-1A). She was treated with retrograde coil embolization of the anterior tibial artery (Figure 36-1B) via a direct exposure of the artery at the ankle. The arteriotomy site was closed with pledgeted sutures. She did well in the postoperative period without any complications. Additional investigation with skin biopsy and collagen electrophoresis analysis that suggested a vascular Ehlers-Danlos syndrome (EDS). She was treated with vitamin C supplements and advised to avoid contact sports and of the need for continued follow-up.

• Heterogeneous group of inherited connective tissue disorders.

• Six main forms of EDS identified with several rare variants.¹

• Majority are autosomal dominant inheritance; some less common forms are autosomal recessive or sex linked.²

• Prevalence of 1/10,000 to 1/25,000.³

• The vascular (AKA type IV or ecchymotic variant) accounts for 5% to 10% of all cases of EDS with a prevalence of less than 1/100,000 overall.^3,4

• The vascular form has the worst prognosis of all forms of EDS with median age of death at 48 years.²

• Genetic defects cause mutations in collagen synthesis.²

• Vascular EDS is associated with type III procollagen deficiencies due to mutations in the COL3A1 gene, resulting in structural defects in the proalpha 1 (proα1) chain of type III collagen^5,6 that leads to extreme vascular fragility.

• The abnormal collagen III molecule cannot fold stably into a triple helix, and is degraded slowly in the rough endoplasmic reticulum of the fibroblast and is never secreted extracellularly. This instability or nonsecretion of mutant protein has been referred to as protein suicide.⁷

• Incomplete penetrance and varying expressivity lead to variations in clinical presentation and symptoms.⁵

• There is a diffuse thinning of the media with reduced elastin and fragmented internal elastic membranes in vessels.³

• Patients with EDS have only a quarter of normal skin thickness so it appears translucent and reveals a network of subcutaneous veins, which is one of the major criterion of affected individuals.

• Vessels have reduced collagen fibril cross-sectional area in the media of the vessel wall as well as reduced collagen content.

• Classical type associated with skin hyperextensibility, joint hypermobility, and skin scarring.^2,6

• Hypermobility type is the most common form and is associated with smooth, velvety skin; joint hypermobility; easy bruising; and frequent inguinal hernias.^2,6

• Vascular type is associated with acrogeria, lobeless ears, and thin, translucent skin in addition to spontaneous arterial and uterine or hollow viscus ruptures.^2,6

• Less common variants include kyphoscoliosis (associated with scleral fragility, joint laxity, and marfanoid habitus), arthrochalasia (congenital bilateral hip dislocation and joint hyper mobility), dermatosparaxis (doughy redundant skin with large umbilical hernias, blue sclera, dwarfism, and severe skin fragility), and several rarer forms.^2,3,6

• A newborn may present with lobeless ears, bulging eyes with telangiectasia on the eyelids, or spontaneous pneumothorax.²

• In pregnancy, uncontrolled uterine hemorrhage necessitating hysterectomy is common. There is a 12% peripartum mortality due to arterial or uterine rupture.² Maternal mortality is approximately 25% with each pregnancy.⁵

• Skin changes include easy and extensive bruising with translucent skin and prominent superficial veins. Joint hypermobility and skin elasticity are not always present.

• Spontaneous colon rupture can occur and is usually of the sigmoid colon.⁴ Only 16% have a diagnosis of EDS prior to a major vascular catastrophe⁴; 80% have a major complication of EDS by the age 40⁸ (Figure 36-2).

• Spontaneous arterial rupture is most common in the abdomen from the splenic or renal arteries rather than the aorta⁶ (Figure 36-2).

• Average age of arterial rupture is 23 years.²

• In addition to spontaneous arterial rupture, individuals can develop multiple aneurysms, arteriovenous (AV) fistulae, and aortic dissection⁶ (Figure 36-3A and B).

• Aneurysm formation is most commonly seen in the visceral, carotid, and aortic arteries.

• AV fistulae are most common at the carotid-cavernous site.

Presence of two or more major criteria is diagnostic of vascular EDS.

• Major criteria: (1) thin and translucent skin; (2) arterial, uterine, or intestine fragility or rupture; (3) easy bruising; (4) characteristic facial appearance—thin nose, thin lips, hollow cheeks

• Minor criteria: acrogeria (taut, thin skin), joint hypermobility, tendon or muscle rupture, club foot, early onset of varicose veins, AV fistula, pneumothorax, gingival recession, family history of sudden death

• Skin biopsy for collagen analysis revealing abnormal electrophoretic mobility.²

• Sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS–PAGE) of fibroblast cultures from skin identifies nearly all individuals with a defect in type III collagen. It can detect quantitative and qualitative defects⁶. (Figure 36-4).

• Sequence analysis testing of mutations for genetic counseling.²

• Family history of sudden death of a close relative in an individual with suspicion for EDS warrants further investigation.

• Coagulation studies, clotting factors, platelet counts, and bleeding times are typically normal.⁶

• Marfan syndrome—defect in fibrillin-1, presents with marfanoid body habitus, lens dislocation, aortic dilatation or dissection, mitral valve prolapsed without increased fragility of smaller arteries and veins.⁶

• Loeys-Dietz syndrome is an autosomal dominant syndrome similar to Marfan syndrome with widely spaced eyes, cleft palate or a bifid uvula, and arterial aneurysms and dissections.^9,10

• Severe bruising in children often leads to a thorough evaluation for hematologic disorders and child abuse.

• Avoid contact sports and weight lifting, and wear protective pads to avoid excessive bruising.

• Vasopressin (DDAVP) can be given to normalize bleeding time via stimulation of von Willebrand factor release if having epistaxis or uncontrolled bruising, or prior to procedures.^4,6

• Ascorbic acid supplementation can help collagen fibril cross-linking, leading to decreased bruising.⁶

• Avoid medications that inhibit platelet function (NSAIDs, aspirin, clopidogrel, penicillins, cephalosporins).⁶

• Prophylactic management of blood pressure to keep systolic less than 120 mm Hg and atherosclerotic disease at a minimum is advised.¹⁰

• The beta-blocker celiprolol in a randomized controlled trial was shown to decrease the rate of spontaneous arterial rupture three fold over a period of 47 months independent of any change in blood pressure or heart rate.¹⁰

• Initial imaging includes echocardiogram, carotid ultrasound, and noninvasive imaging of the chest and abdomen.⁸

• Suggested follow-up for asymptomatic patients includes annual physical examination, carotid ultrasound, and noninvasive imaging of the chest and abdomen. If a patient has developed symptoms he or she needs closer follow-up every 3 to 6 months with imaging.⁸

• Genetic counseling is mandatory. Vascular-type EDS is inherited in an autosomal dominant fashion, so the child of an affected parent has a 50% likelihood of inheriting EDS.

• Avoid diagnostic angiography or other invasive testing as lethal hemorrhage can occur. Arteriography is associated with a 22% to 67% complication rate and 5% to 16% mortality.^4,10,12 Recent reports suggest access site complications of less than 2% for endovascular procedures (combined diagnostic or interventions in both arterial and venous systems).¹³

• If angiography is required then it should be performed with vessel exposure so as to repair the vessel directly.

• Anesthetic considerations should include avoiding central venous lines, placing arterial lines, intramuscular injections, cross-matching adequate blood, and gentle intubation.

• Surgical intervention should be avoided unless absolutely warranted. When intervention is necessary for ruptured pseudoaneurysms, visceral artery aneurysms, and carotid-cavernous fistulas, endovascular coil embolization should be the initial treatment of choice. Successful embolization of aortic branch vessels has been reported.¹⁰

• When feasible a transvenous access approach is associated with fewer complications. Open closure of approach sites should be performed to lessen the risks from the access site.

• Stent grafting is contraindicated in connective tissue disorders¹⁰ due to long-term durability concerns as well as threat to fixation zones in the setting of chronic outward radial force as this may increase the frequency of secondary interventions.

• Uncontrollable hemorrhage can occur with gentle placement of vascular clamps. Vascular occlusion, when possible, should be accomplished with tourniquets.⁴ When not possible, shodded or soft-jawed vascular clamps should be used.¹²

• The surgical treatment of choice for vascular lesions is ligation with reconstruction offered only when essential and when the risks are carefully explained to the patient (Figure 36-5A,B and C). Ligation should be performed even when sacrifice of a limb or nonessential organ will result.⁴

• Reinforcement of sutures and ligation sites is essential. A cuff of polytetrafluoroethylene or comparable material should be placed over all anastomoses.⁴

• Mortality from a vascular rupture is 44% prior to surgical intervention, and another 19% do not survive the operation and immediate postoperative course. Mortality from a hollow viscus rupture is 20%.⁴

• http://www.ncbi.nlm.nih.gov/pubmed/19879095

• http://www.jvascsurg.org/article/S0741-5214(07)00522-8/abstract

• www.ednf.org

• www.ehlersdanlosnetwork.org