DISEASE CARD

Definition

EDS vascular type (vEDS) is characterized by arterial and gastro-intestinal rupture, rupture of the gravid uterus and extensive bruising. It is caused by mutations in the COL3A1 gene encoding type III collagen (2q32.2) and rarely by specific heterozygous arginine-to-cysteine substitution mutations in COL1A1.^{1, 2} Transmission is autosomal dominant. One vEDS patient has been reported with autosomal recessive mode of inheritance.^{3, 4}

Clinical Description

Of all EDS subtypes, vEDS has the worst prognosis because of the risk of potentially fatal vascular and intestinal complications. Tissues with abundant type III collagen (blood vessels, bowel, uterus) are most affected. Excessive bruising is the most common sign and might be mistaken for child physical abuse. A history of gingival bleeding (aggravated by periodontal disease and gingival recession), especially following brushing the teeth, or profuse bleeding after tooth extraction is commonly present. Hematologic evaluation does not show any abnormalities. Other early manifestations include obstetric problems (e.g. premature rupture of the membranes), congenital club foot or congenital hip dislocation and spontaneous and/or recurrent pneumothoraces.⁵

Unlike in other EDS subtypes, the skin is not hyperelastic but thin and translucent, with readily visible veins on the torso, dorsum of hands and extremities. Wrinkling and thinness of the skin of extremities may produce an aged appearance (acrogeria). Unusual cutaneous manifestations include elastosis perforans serpiginosa, keloid formation and Raynaud phenomenon. Patients with vEDS often have a characteristic facial appearance, including prominent eyes (due to lack of subcutaneous adipose tissue), a thin, pinched nose and small lips, hollow cheeks and lobeless ears.⁶

Hypermobility is usually limited to the small joints of the hands.

The vascular fragility largely dominates the clinical picture, leading to precocious and severe varicoses and arterial rupture or dissection. These complications occur often unexpected, presenting as acute abdomen, cerebral stroke, hematemesis, renal colic and hematuria, retroperitoneal bleeding, muscle swelling, shock and sudden death, as early as in the third or fourth decade of life. The most common locations of arterial bleeding are the thorax and abdomen (66%), head and neck (17%) and extremities (17%) and involve medium-sized arteries (abdominal mesenchymal, splenic, renal arteries, descending aorta). Aneurysm, arteriovenous fistulae or dissection may precede arterial rupture.⁶

Gastro-intestinal perforation is common (approximately in 15%), mostly occurring in the sigmoid colon. It is rarely lethal (3%), however, complications during and following surgery to perforation repair are frequent and related to tissue and vessel friability, resulting in recurrent arterial or bowel tears, fistulae, poor wound healing, and suture dehiscence.⁶

Obstetrical complications include vascular, intestinal or uterine rupture, vaginal lacerations, prolapse of uterus and bladder, and premature delivery because of cervical insufficiency or fragility of the membranes. Patients with a vascular EDS who are pregnant or contemplate pregnancy should be followed in a high-risk obstetrical program. With early caesarean section, severe lacerations may be avoided.^{4, 6, 7}

Life-threatening complications, that rarely occur in childhood but in 25% by the age of 20 years, cause a median survival of 51 years.⁴

Diagnostic Criteria

Major criteria

• Family history of vEDS with documented causative variant in COL3A1
• Arterial rupture at a young age
• Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology
• Uterine rupture during the third trimester in the absence of previous C‐section and/or severe peripartum perineum tears
• Carotid‐cavernous sinus fistula (CCSF) formation in the absence of trauma

Minor criteria

• Bruising unrelated to identified trauma and/or in unusual sites such as cheeks and back
• Thin, translucent skin with increased venous visibility
• Characteristic facial appearance
• Spontaneous pneumothorax
• Acrogeria
• Talipes equinovarus
• Congenital hip dislocation
• Hypermobility of small joints
• Tendon and muscle rupture
• Keratoconus
• Gingival recession and gingival fragility
• Early onset varicose veins (under age 30 and nulliparous if female)

Minimal criteria suggestive for vEDS:

A family history of the disorder, arterial rupture or dissection in individuals less than 40 years of age, unexplained sigmoid colon rupture, or spontaneous pneumothorax in the presence of other features consistent with vEDS should all lead to diagnostic studies to determine if the individual has vEDS. Testing for vEDS should also be considered in the presence of a combination of the other “minor” clinical features listed above. The diagnosis of vEDS rests on the identification of a causative variant in one allele of COL3A1.

Even for experienced clinicians the clinical diagnosis of vEDS may be difficult. Because of implications for treatment, natural history, and recurrence risk, the diagnosis of vEDS rests on the identification of a causative variant in one allele of COL3A1.

Pathogenesis

The condition is primarily caused by mutations in the COL3A1 gene, coding for the a1 chain of type III collagen. This homotrimer is a major structural component of skin, blood vessels, and hollow organs. Mutations causing abnormal structure, synthesis or secretion of a1 chain of type III collagen result in a thin dermis with variable size of collagen fibrils.To date more than 250 COL3A1 mutations have been identified. These include point mutations leading to substitutions for glycine in the triple helical region of the collagen molecule, splice site mutations resulting in exon skips, intron inclusion or complex and multiple outcomes, partial gene deletions, and, less commonly mutations resulting in haplo-insufficiency. Arterial complications are less likely in mutations located in the C- or N-termini or those resulting in haploinsufficiency.^8-10

Arginine-to-cysteine substitution mutations in COL1A1 ((c.934C>T, p.Arg312Cys; c.1720C>T, p.Arg574Cys and c.3277C>T, p.Arg1093Cys) may also result in an EDS phenotype with propensity to arterial rupture in early adulthood. Vascular EDS is an autosomal dominant disorder, but parental somatic mosaicism for COL3A1 mutations have been documented.^{2, 11}

One case of autosomal recessive inheritance of vEDS has been reported. In a young consanguineous girl of healthy parents a homozygous nucleotide duplication was found, that resulted in a premature termination codon and consequently in nonsense-mediated mRNA decay.₃

Diagnosis

The diagnosis is based on family history and clinical findings (see clinical diagnostic criteria). Molecular screening by Sanger sequencing of COL3A1, or targeted resequencing of a gene panel that includes COL3A1 and COL1A1 (the latter to identify the above‐listed arginine‐to‐cysteine substitution mutations) should be performed. A CNV detection strategy to identify large deletions or duplications is indicated when molecular screening is negative. However, especially if alternative diagnoses are unlikely, that standard diagnostic molecular procedures might not detect all mutations (e.g., deep intronic mutations).⁸

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Treatment

See article "Ehlers Danlos Syndrome"

Individuals with vascular EDS should avoid contact sports or isometric exercises (weightlifting) and other activities that raise intracranial pressure by the Valsalva effect, drugs that interfere with platelet function, and anti-coagulation therapy. Control of the blood pressure and treatment with celiprolol, a cardioselective β1 blocker with vasodilatory effect, for changing the rate of arterial complications seem to be beneficial. Invasive vascular procedures such as arteriography and catheterization should be avoided, whenever possible and replaced by ultrasonography and/or non-invasive imaging. Surgical interventions are generally discouraged due to associated risks, and conservative therapy is recommended. If surgery is unavoidable, manipulation of vascular and other tissues should be done with extreme care. In case of bowel rupture, prompt surgical intervention is necessary and life-saving. Pregnant women with the vascular type of EDS should be closely monitored in a high-risk obstetrical program.^{12, 13}

References