Ehlers-Danlos Syndrome, Vascular (type 4)
Ehlers-Danlos syndrome is a condition that affects connective tissue --- particularly, collagen. Collagen is an abundant structural protein found in muscles, tendons, skin and bones. It can be thought of as both holding the body together and strengthening it.
There are many subtypes of EDS. Although there are many differences between them, two clinical features occur in all forms of EDS. The first is joint hypermobility (often called loose or double joints). People with EDS can often move their joints in ways that are impossible for most unaffected people (see the photograph on this page). However, many people without EDS have loose joints, and having joint hypermobility does not mean that person has a medical disorder. The second clinical feature that occurs in every form of EDS is hyperextensible (stretchy) skin. In some forms (classic and kyphoscoliotic, for example), this feature is nearly universal. In our literature survey for our software tool, we found that stretchy skin occured in less than half of people with the hypermobile and vascular forms, more than half of patients with the periodontitis type, and in a large majority of people with the arthrochalasia type (>80%).
Joint laxity/hypermobility is usually assessed with a scoring system called the Beighton score, which was developed in the early 1970s (1). This simple system scores a person's ability to move a joint past certain angles. The highest score is 9 points, and higher scores mean greater joint laxity. Generally speaking, scores of 4 or higher (at any time, past or present) in persons under age 50 indicate joint hypermobility. Many EDS patients have scores of 8 or 9, although many have lower scores, and a minority do not have hypermobile joints. Interested readers may wish to see a basic description of the scale with a video and photos or a more technical description.
The joint laxity that is common in EDS puts patients at high risk for joint dislocations and subluxations. These problems can be painful, and in some cases, debilitating. Surgical procedures have been used to improve skeletal stability and improve quality of life; for examples and reviews, see references 2-4.
The EDS syndromes as a group also have a classification system. This sytem is called the Villefranche classification. Villefrance uses descriptive terms for different types of EDS (e.g. vascular, kyphoscoliotic). These terms are the formally accepted names for each type of EDS. Before the Villefanche classification, the different forms of EDS were numbered (type 1, type 2, etc). These numbers are still in common use today. As a result, we have included them here. Type 8 is officially referred to as the periodontitis type of EDS, but continues to be generally referred to as type VIII in the literature. We will use the numbered term here (though with the numeral 8).
The Villefranche system classifies the different forms of EDS based on clinical and, when possible, molecular criteria. Unfortunately, some forms of EDS have not yet been associated with mutations in any genes. In addition, different disorders can be caused by mutations in the same genes. The situation can be complex, but research aimed at fully understanding it is ongoing.
Tissue fragility is another common feature of EDS. This problem is very serious in the vascular type of EDS; patients with this form of EDS are at high risk for spontaneous ruptures of large blood vessels and bowel perforations. Surgery on a person with this type of EDS must be performed with great care as a result of this problem. People with the hypermobile form are also prone to blood vessel ruptures, they though tend to occur in the small blood vessels of these patients. Tissue fragility can also lead to hernias and problems in pregnancy. Fragile skin is also a common manifestation of EDS, especially in people with the classic, kyphoscoliotic, and periodontitis types.
EDS affects women more commonly than men. We decided to count the number of male and female patients while we were characterizing six different types of EDS for our diagnostic aid software. Altogether, we analyzed data from ~1,100 patients. Sex information was available for 1,075. The table below shows that although more EDS patients are women in each type of EDS, the female:male ratio varies between each type. For example, females dominated the individuals reported with the hypermobility type, while males comprised a substantial minority of kyphoscoliotic and arthrochalasia patients. The distribution was roughly even in EDS type 8. However, the low number of case reports for these three types of EDS may have affected the outcome of this small analysis.
Above: Percentages of male and female patients with different types of EDS. Source: V. Natale & FDRF.
According to NIH's Genetics Home Reference (see link at right), the prevalence of all forms of EDS is roughly 1 in 5,000 worldwide. The vascular type (VEDS) is an uncommon form, comprising an estimated 5-10% of all EDS cases (5). The Gene Review article estimates that its prevalence may be 1 person in 50,000, and that this estimate may be low due to mild cases being undiagnosed.
VEDS is a severe form of EDS that may also go undiagnosed until after death. Its most important feature is fragility of the blood vessels, intestines, and/or uterus. Because the disease is often not diagnosed in a timely manner, patients often present with gastrointestinal perforations, organ ruptures, or ruptured blood vessels. In some cases, these problems can occur during surgery, resulting in fatalities. Patients also have a tendency to prolonged bleeding, in spite of no coagulation abnormalities (5). Bleeding may result from activities as benign as brushing teeth. This problem, in combination with increased tissue fragility, can also create complications during surgery. Surgeons may be unable to suture internal tissues, resulting in blood loss that may be fatal.
Vascular ruptures, vascular dissections, and organ ruptures are serious problems in VEDS. They may occur spontaneously, and vascular ruptures may occur after aneurysms and other problems. Beighton (6) described a case of a 7-year-old boy with EDS4. While sitting in school, he suffered sudden pain due to peritonitis that was secondary to perforation of the colon. His colon ruptured again at age 10, and he died at age 14 of sudden tearing in large arteries. He was also described as being prone to skin lacerations "at the slightest provocation." Because of the possibility of these types of problems, people with VEDS are encouraged to seek medical attention immediately if they experience sudden, unexplained pain.
In addition, periodic monitoring with non-invasive scanning equipment is critically important in this condition. A recent review on VEDS states that arterial ruptures and dissections (tears in the lining of an artery) are both unpredictable and the cause of a majority of deaths in VEDS (7). The fragility of the blood vessels makes them difficult to repair surgically. These problems tend to occur in large- and medium-sized arteries (7), with the following are often involved:
- Proximal branches of the aorta
- Descending thoracic aorta
- Renal, mesenteric, iliac, or femoral arteries
In addition, pregnant women with VEDS should be monitored carefully, as complications, including mortality due to rupture of the uterus, are increased over the general population (8).
Joint hypermobility in VEDS patients tends to occur mainly in the small joints, and the skin is not as stretchy/hyperextensible as it is in patients with other forms of EDS (see photos below). Patients may also have acrogeria, which is a prematurely aged appearance of the extremities (see photo below).
Some patients with VEDS have a distinctive facial appearance (see photos at top right and below). These feature include large eyes, thin lips, a thin or pinched nose, blue sclera, and underdeveloped earlobes. Otherwise, the most common signs and symptoms of this condition are as follows:
- Fragile blood vessels that are prone to rupturing
- Aneurysms or false aneurysms
- Fragile skin that may lacerate after very minor trauma
- Wounds that heal poorly after injury or stitching/suturing
- Scars that may be deeply pigmented
- Acrogeria (premature aging of the extremities; see photo below)
- Easy bruising (may occur without injury/trauma)
- Mildly stretchy skin that appears normal after being released
- Joint hypermobility of the small joints
- Flat feet
Signs and symptoms of vascular EDS
Diagnosis and Testing
VEDS is an autosomal dominant disorder. This term means that it can be passed from one affected parent to a child. This mode of transmission occurs in roughly half of patients. In the others, the mutation arises spontaneously in families without an affected parent. Mutations in a gene called type 3 collagen (COL3A1) are the only known causes of VEDS. The link at the right provides information about labs that test for mutations in this gene.
It is important to remember that there is considerable overlap between the different forms of EDS. This fact means that, in the absence of laboratory testing, accurate subcategorization of EDS in a patient may be difficult or even impossible. This fact makes testing important; it is especially so in the case of VEDS, which involves so many potentially fatal complications.
The differential diagnosis for vascular EDS includes the other forms of EDS. In particular, clinical findings in in vascular EDS overlap with those of the classic form of EDS (formerly types 1 and 2). Most EDS-classic patients have mutations in the genes COL5A1 or COL5A2, which encode type 5 collagen, although COL1A2 is mutated in a minority of cases. Clinicians may also wish to test for the kyphoscoliotic form of EDS.
Overall, joint hypermobility occurs in a variety of medical conditions, and many people without a medical condition have lax joints. In fact, when not part of a disorder, hypermobile joints confer an advantage in sports such as gymnastics and ice skating, as well as in certain forms of dance.
Marfan syndrome. Most medical conditions involvong lax joints are relatively easy to distinguish from EDS, but some are not. Marfan syndrome is an example. Like EDS, Marfan syndrome is a connective tissue disorder and patients have lax joints. Marfan patients generally have a body type called a Marfanoid body habitus. This term means that a person is tall and slender, with long arms, hands, fingers, legs, feet and toes. A Marfanoid body habitus occurs in a minority of EDS-H patients, but it does not appear to be generally associated with classic EDS. The Marfan Foundation has many photographs of Marfan patients of different ethnicities. Unlike EDS patients, Marfan patients do not appear to have fragile skin and blood vessels.
Cutis laxa. Superficially, the stretchy skin found in most forms of EDS may be confused with cutis laxa type 1 and type 2, as stretchy skin is also a feature of these conditions. However, the skin in cutis laxa patients tends to sag and does not return to its normal position after being extended. Cutis Laxa patients often have a prematurely aged appearance.
The Gene Review on vascular EDS (see link at right) has a list of other conditions that are part of the differential diagnosis for EDS. They include Loeys-Dietz syndrome, Stickler syndrome, and a number of others. In addition, Because they bruise so easily and experience joint dislocations and subluxations, very young VEDS patients may be suspected of child abuse.
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