Vascular Ehlers-Danlos Syndrome

Excerpt

Clinical characteristics: Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication.

Diagnosis/testing: The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic variant in COL3A1.

Management: Treatment of manifestations: Creation of an organized care team is one of the first tasks to complete upon the initial diagnosis. The team should include a primary care physician, vascular surgeon, general surgeon, cardiologist, pulmonologist, and geneticist. Affected individuals should carry documentation of their genetic diagnosis, such as a MedicAlert^® bracelet or necklace, an emergency contact letter, or vEDS "passport." Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain, coordinated through the primary care physician when possible. Treatment may include medical or surgical management for arterial complications, bowel rupture, or uterine rupture during pregnancy.

Surveillance: May include periodic arterial screening by ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast. Blood pressure monitoring on a regular basis is recommended to allow for early treatment if hypertension develops.

Agents/circumstances to avoid: Trauma (collision sports, heavy lifting, and weight training with extreme lifting); arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury; routine colonoscopy in the absence of concerning symptoms or a strong family history of colon cancer; elective surgery unless the benefit is expected to be substantial.

Evaluation of relatives at risk: It is appropriate to evaluate first-degree relatives in order to identify as early as possible those who could benefit from surveillance, awareness of treatment for potential complications, and appropriate restriction of high-risk physical activities; evaluation usually starts with clinical assessment and, even in the absence of clinical signs, progresses to molecular genetic testing for the known familial pathogenic variant.

Pregnancy management: Affected women have a 5% mortality risk with each pregnancy. The issue of management and recommendations is complicated by the recognition that many of the women who became pregnant, and their providers, learn of the diagnosis at the time of delivery and the onset of complications. In pregnant women with a known diagnosis, maternal risks should be discussed, and these women should be followed in a high-risk obstetric program. Management decisions about nature and timing of delivery can be stratified by the nature of the genetic alteration.

Genetic counseling: Vascular EDS is an autosomal dominant disorder. About 50% of individuals diagnosed with vEDS have an affected parent; about 50% of affected individuals have the disorder as the result of a COL3A1 pathogenic variant that occurred as a de novo event in the individual or as a de novo event in an apparently unaffected, mosaic parent. Each child of an individual with vEDS has a 50% chance of inheriting the pathogenic variant and developing complications of the disorder. Once the COL3A1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for vEDS are possible.