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, or, when molecular genetic testing does not identify a COL3A1 pathogenic variant, on biochemical analysis of type III procollagen from cultured fibroblasts.

Management.

Treatment of manifestations: Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain. 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: The genetic status of at-risk relatives should be clarified through molecular genetic testing or clinical evaluation if the pathogenic variant is unknown.

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. When the mother’s diagnosis is known, maternal risks should be discussed and she should be followed in a high-risk obstetric program.

Other: Affected individuals should carry documentation of their genetic diagnosis, such as a MedicAlert^®, emergency letter, or vEDS "passport."

Genetic counseling.

Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. About 50% of affected individuals have inherited the COL3A1 pathogenic variant from an affected parent, and about 50% of affected individuals have a de novo pathogenic variant. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing the disorder. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible in families in which the pathogenic variant in COL3A1 has been identified.

Suggestive Findings

Vascular Ehlers-Danlos syndrome (vEDS) should be suspected in individuals with any one of the following major diagnostic criteria or several minor diagnostic criteria, particularly in those younger than age 40 years. Clinical diagnostic criteria established in 2017 [Malfait et al 2017] are useful to guide the approach to genetic testing.

Major diagnostic criteria

• Arterial aneurysms, dissection, or rupture
• Intestinal rupture
• Uterine rupture during pregnancy
• Family history of vEDS

Minor diagnostic criteria

• Thin, translucent skin (especially noticeable on the chest/abdomen)
• Characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes)
• Acrogeria (an aged appearance to the extremities, particularly the hands)
• Carotid-cavernous sinus arteriovenous fistula
• Hypermobility of small joints
• Tendon/muscle rupture
• Early-onset varicose veins
• Pneumothorax/hemopneumothorax
• Easy bruising (spontaneous or with minimal trauma)
• Chronic joint subluxations/dislocations
• Congenital dislocation of the hips
• Talipes equinovarus (clubfoot)

Establishing the Diagnosis

The diagnosis of vEDS is established in a proband with either of the following:

• Identification of a heterozygous pathogenic variant in COL3A1 on molecular genetic testing (See Table 1.)
• Abnormalities in synthesis and mobility of type III collagen chains on biochemical analysis of type III procollagen from cultured fibroblasts when vEDS is suspected but molecular genetic testing does not identify a COL3A1 pathogenic variant

Note: (1) When the diagnosis is suspected on clinical grounds, molecular diagnostic testing of COL3A1 is indicated. (2) The presence of clinical phenocopies and variable expression of the vEDS phenotype warrant the molecular diagnostic approach.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of vEDS is broad, individuals with the distinctive major criteria findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited connective tissue disorders are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The most comprehensive descriptions of clinical features and natural history derive from two types of studies: a cross-sectional and retrospective view obtained at the time of diagnostic testing [Pepin et al 2014] and a nearly 15-year-long cohort study from one group in France [Frank et al 2015]. A retrospective review of the health history of more than 1,200 individuals with vascular Ehlers-Danlos syndrome (vEDS) delineated the natural history of the disorder [Pepin et al 2014]. The majority of individuals were ascertained on the basis of a major complication (70%), at an average age of 30 years. Median survival in the population was 50 years, with a younger median survival in males (by 5 years) than in females, partially due to a higher rate of lethal vascular events in males than females before age 20 years. A similar rate of complications was reported in the French cohort of 215 individuals with vEDS, but a difference in mean survival based on sex was not observed [Frank et al 2015].

Genotype-Phenotype Correlations

More than 600 unique COL3A1 pathogenic variants have been aggregated into the Ehlers Danlos Syndrome Variant Database with an additional 250 in ClinVar. Approximately 5% of COL3A1 variants result in haploinsufficiency. Individuals with a COL3A1 null variant have a 15-year delay in onset of complications, improved life expectancy (close to that of the US population), and significantly fewer obstetric and bowel complications than are seen with other types of COL3A1 pathogenic variants [Leistritz et al 2011, Pepin et al 2014, Frank et al 2015].

Among the 1,200 individuals with vEDS described by Pepin et al [2014], survival depended in part on the nature of the pathogenic variant. Survival was longest for those with a null variant and shortest for those with a splice donor site variant that resulted in exon skipping or a substitution for a triple helical glycine residue (in the repeating Gly-Xaa-Yaa triplets) by a large residue. The location of the variant within the triple helix did not have a discernable effect on survival. Similar survival patterns were described in the French cohort of 126 individuals with COL3A1 pathogenic variants [Frank et al 2015]. These differences in populations are difficult to use to counsel individuals because of significant intra- and interfamilial variability in age of complication and survival for the same pathogenic variant.

Penetrance

In families identified on the basis of clinical complications, penetrance of the vEDS phenotype appears to be close to 100% in adults with a missense or exon-skipping alteration; the age at which the pathogenic variant becomes penetrant may vary. COL3A1 null variants have significantly reduced penetrance manifested by the absence of minor diagnostic criteria in 51% of individuals with vEDS identified with a pathogenic null alteration [Leistritz et al 2011].

Nomenclature

The following terms for vEDS have been used:

• Ehlers Danlos syndrome type IV was introduced by Beighton in his 1979 summary of heterogeneity in Ehlers Danlos syndrome.
• Status dysvascularis was introduced by Georg Sack in 1936; the term was never used extensively.
• Familial acrogeria, introduced by Heinrich Gottron in 1940, probably included some individuals with vEDS.
• Sack-Barabas syndrome or the Sack-Barabas type of Ehlers-Danlos syndrome was used after Barabas [1967] introduced the disorder to the English-language literature.

Prevalence

There are no good estimates of the prevalence of vEDS in any population. About 1,500 affected individuals in the United States have been identified on the basis of biochemical and genetic testing and analysis of family pedigrees [Author, personal observation], leading to a minimum prevalence estimate of 1:200,000. The decreased frequency of certain classes of pathogenic variants suggests that the overall prevalence of individuals with pathogenic variants in COL3A1 (see Molecular Genetics) could approach that of individuals with pathogenic variants in COL1A1, which is estimated at close to 1:50,000.

Because many families with vEDS are identified only after a severe complication or death, it is likely that individuals/families with pathogenic variants in COL3A1 and a mild phenotype do not come to medical attention and thus go undetected. In addition, because of the perceived rarity of the disorder, it is seldom considered and nonvascular complications may not raise diagnostic suspicion of vEDS.

Evaluations Following Initial Diagnosis

There is currently no consensus regarding the appropriate extent of evaluation at the time of initial diagnosis. To establish the extent of disease and needs in an individual diagnosed with vEDS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Because of the risk for asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken [Chu et al 2014, Frank et al 2015]; the approach employed varies by geographic region and by institution (see Surveillance). Approach to a vascular evaluation depends on the age of the patient and the circumstances in which the diagnosis is made.
• Because no specific gastrointestinal findings are known to precede or predict bowel rupture, invasive GI evaluation is of no benefit.
• Consultation with a clinical geneticist and/or genetic counselor is recommended.
• Following diagnosis, the most crucial aspect of management is the creation of an organized care team. See Treatment of Manifestations.
• Review lifestyle with the affected individual and emphasize the importance of minimizing collision activities and sports.

Treatment of Manifestations

The most crucial aspect of management is the creation of an organized care team that includes a primary care physician, vascular surgeon, and general surgeon; a geneticist may aid in integration of care. This team is responsible for the organization of ordinary and extraordinary care. In addition, individuals with vEDS should carry documentation of their genetic diagnosis, such as a MedicAlert^®, emergency letter, or vEDS "passport."

Affected individuals should be instructed to seek immediate medical attention for sudden, unexplained pain.

Surgical intervention may be lifesaving in the face of bowel rupture, arterial rupture, or organ rupture (e.g., the uterus in pregnancy).

• When surgery is required for treatment, it is appropriate to target the approach and minimize surgical exploration because of the risk of inadvertent damage to other tissues [Oderich et al 2005]. In addition, an approach of "judicious underhydration" may help to prevent the recognized cycle of complications.
• In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of vEDS and its associated tissue fragility [Shalhub et al 2014].

There are no guidelines to direct recommendations for elective repair in individuals with aneurysm(s) and vEDS.

• A decision about the timing and approach of an elective vascular procedure or the use of endovascular approaches is typically based on an individualized risk/benefit assessment.
• Reports of successful endovascular approaches are growing but no studies have compared outcomes with endovascular vs open repair.

Prompt surgical intervention of bowel rupture is usually essential to limit the extent of infection and facilitate early restoration of bowel continuity.

• Death from bowel rupture is uncommon because intervention is generally effective.
• Bowel continuity can be restored successfully in most instances, usually three to six months after the initial surgery.
• The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend partial or total colectomy to reduce the risk of recurrent bowel rupture [Frank et al 2015].
  Some physicians and affected individuals consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [Fuchs & Fishman 2004].

Surveillance

The use of surveillance of the arterial vasculature assumes that effective interventions will decrease the risk of arterial dissection or rupture and prolong life. At a time when an open surgical approach was the only option, the benefit of surveillance could not be established. As endovascular approaches to management of aneurysms and dissection become more available, earlier intervention is considered and surveillance is seen to have greater benefit. There are, however, no published data assessing the efficacy of screening strategies in identifying the regions in the arterial vasculature at highest risk; conversely, there are examples in which regions of concern in the arterial vasculature failed to progress and arterial rupture occurred at other more distant sites. Thus, the benefit of controlled studies cannot be overemphasized.

If undertaken, noninvasive imaging such as ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast is preferred to identify aneurysms, dissections, and vascular ruptures [Chu et al 2014]. Because arterial tear/dissection may result at the site of entry of the catheter and at sites of high-pressure injection, conventional arteriograms are not recommended. When surveillance is undertaken, repeat measure depends on the pathology identified, but in the presence of a normal vascular tree, screening at 18-month intervals appears to be the usual practice.

Blood pressure monitoring on a regular basis is recommended to allow for early treatment if hypertension develops, thus reducing the risk for vascular stress and injury.

Agents/Circumstances to Avoid

Trauma. Because of inherent tissue fragility, it is prudent for individuals with vEDS to avoid collision sports (e.g., football), heavy lifting, and weight training with extreme lifting. Of note, no evidence suggests that moderate recreational exercise is detrimental.

Arteriography. Conventional arterial angiography (with contrast injection) should be discouraged because it has been associated with added de novo complications [Zilocchi et al 2007]. Arterial tear/dissection may result at the site of entry of the catheter; furthermore, injection pressure may lead to arterial aneurysms. Arteriography is currently best used as part of a planned interventional procedure, such as coil embolization or stenting of bleeding arteries.

Routine colonoscopy. There are several reports of colonoscopy-associated bowel perforation in individuals with vEDS. Virtual colonoscopy, which also involves insufflation, may have similar complications. Routine colonoscopy for cancer screening is discouraged in the absence of concerning symptoms or a strong family history of colorectal cancer. Individuals with vEDS who have a family history of colon cancer are encouraged to use genetic testing for colon cancer risk assessment (provided the genetic etiology of colon cancer has been established in an affected family member). Use of capsular cameras may provide sufficient data in at-risk individuals.

Elective surgery. Because tissue fragility results in a higher risk of surgical complications, elective surgery for individuals with vEDS is generally discouraged unless the benefit is expected to be substantial. In general, avoidance of surgery in favor of more conservative management is advised, although data about elective surgery are just beginning to emerge and this approach needs to be reevaluated.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual 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. Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• Clinical evaluation if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality. The most extensive study, which included evaluation of more than 500 pregnancies in 253 women [Murray et al 2014], found a mortality rate of about 5% per pregnancy. This is lower than previously identified and may be because a significant number of the women included knew about the diagnosis before pregnancy or delivery. The issue of management and recommendations is complicated by the recognition that many of the women who became pregnant, and their providers, learned of the diagnosis at the time of delivery and the onset of complications.

About half the women in the study had no complications. For others, prematurity, and uterine, cervical, and vaginal tears led to morbidity.

Increasingly, the practice is to plan delivery by cesarean section at 36-38 weeks to try to avoid the extensive tissue injury that can accompany vaginal delivery. This procedure can be associated with an increased risk of hemorrhage and inadvertent damage to nearby abdominal organs.

When the diagnosis is known in the mother, the maternal risks should be discussed and all options considered. The decision to proceed with pregnancy should involve enlarging the care team to include a high-risk obstetric service. Plans for early delivery should include the presence of the vascular surgeon and potentially the general surgeon.

It is essential to educate the pregnant woman regarding possible complications and the need for close monitoring.

Therapies Under Investigation

A clinical trial in France to determine if addition of an angiotensin receptor blocker to celiprolol decreases arterial complications and extends life expectancy is currently underway.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Vascular Ehlers-Danlos syndrome (vEDS) is almost always inherited in an autosomal dominant manner. There are rare reports of individuals with biallelic pathogenic variants in COL3A1 [Jørgensen et al 2015].

Risk to Family Members

Parents of a proband

• About 50% of individuals diagnosed with vEDS have an affected parent.
• A proband with vEDS may have the disorder as the result of a de novo COL3A1 pathogenic variant. The proportion of affected individuals with a de novo pathogenic variant is about 50%.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include physical examination and molecular genetic testing.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or mosaicism in a parent.
  • The estimated rate of parental somatic and germline mosaicism is 2%-5%. To date, parents mosaic for a COL3A1 pathogenic variant are not known to be symptomatic or to have had complications compatible with the diagnosis of vEDS, though further investigation is needed [Legrand et al 2019].
  • Two families in which there appears to be isolated germline mosaicism have been identified [Byers et al 2003, Palmeri et al 2003].
• The family history of some individuals diagnosed with vEDS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the COL3A1 pathogenic variant identified in the proband, the risk to each sib is 50%.
• If the proband has a known COL3A1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to the sibs is about 1% because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the COL3A1 pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for vEDS because of the possibility of reduced penetrance in a parent or parental germline mosaicism.

Offspring of a proband

• Each child of an individual with vEDS has a 50% chance of inheriting the pathogenic variant and developing complications of the disorder.
• In the rare occurrence in which an individual has biallelic COL3A1 pathogenic variants, 100% of offspring will inherit one of the variants and may be symptomatic.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, additional explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of asymptomatic individuals younger than age 18 years

• The benefits of testing individuals younger than age 18 years for vEDS include: (1) elimination of concern for those children who do not have the familial pathogenic variant; (2) awareness of and preparedness for potential complications; and (3) restriction of high-impact sports and high-risk activities for those with the pathogenic variant.
• Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years [Pepin et al 2014, Frank et al 2015]. Genetic testing of at-risk children has been controversial because of the concern that there is no preventive treatment. However, awareness of the condition is a key component of appropriate intervention in the occurrence of a major complication and for implementation of risk-reducing behaviors. In this context, 87% of children tested before age 18 years had not experienced a major complication and the mean age of testing was eight years. Given the opportunity to consider testing for children at 50% risk of having inherited the pathogenic variant, parents usually did not wait until a complication arose or until the child reached majority for a test to be performed. Instead, they requested that the test be performed to clarify the child's status and allow them to anticipate medical risks [Author, personal communication].

In a family with an established diagnosis of vEDS it is appropriate to consider testing symptomatic individuals regardless of age.

For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for vEDS are possible. Given the efficiency of molecular genetic testing and the recognition that essentially all individuals with a biochemical diagnosis of vEDS also have a known COL3A1 pathogenic variant, molecular genetic testing is the recommended approach for prenatal testing. Experience with use of assisted reproductive technologies for women with vEDS is limited [Bergeron et al 2014].

Biochemical testing. In rare families in which only the biochemical abnormality of type III collagen is known, analysis of cultured CVS cells can be used as an alternative to molecular genetic prenatal testing. Biochemical testing for prenatal diagnosis of vEDS should be performed only if the molecular etiology cannot be identified.

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 8-30-21. [PubMed: 23428972]
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2019. Accessed 8-30-21.

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Author Notes

Collagen Diagnostic Laboratory website

Author History

Peter H Byers, MD (1999-present)
Mitzi L Murray, MD, MA; University of Washington (2015-2019)
Melanie G Pepin, MS, CGC; University of Washington (1999-2019)

Revision History

• 21 February 2019 (ha) Comprehensive update posted live
• 19 November 2015 (me) Comprehensive update posted live
• 3 May 2011 (me) Comprehensive update posted live
• 7 June 2006 (me) Comprehensive update posted live
• 25 January 2005 (cd) Revision: change in availability of clinical testing
• 14 April 2004 (me) Comprehensive update posted live
• 15 April 2002 (me) Comprehensive update posted live
• 2 September 1999 (me) Review posted live
• 6 April 1999 (mp) Original submission