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Vascular Ehlers-Danlos Syndrome

Synonyms: EDS Type IV; Ehlers-Danlos Syndrome, Vascular Type; vEDS

, MS, CGC, , MD, MA, and , MD.

Author Information
, MS, CGC
Collagen Diagnostic Laboratory
University of Washington
Seattle, Washington
, MD, MA
Departments of Pathology and Medicine
University of Washington
Seattle, Washington
, MD
Departments of Pathology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: November 19, 2015.

Summary

Clinical characteristics.

Vascular Ehlers-Danlos Syndrome (vEDS) is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. Neonates may present with clubfoot and/or congenital dislocation of the hips. In childhood, inguinal hernia, pneumothorax, recurrent joint subluxation or dislocation, and bruising can occur. Pregnancy for women with vEDS has an estimated 5.3% risk for death from peripartum arterial rupture or uterine rupture. One fourth of individuals with vEDS, confirmed by laboratory testing, experienced a major complication by age 20 years and more than 80% by age 40 years. The median age of death in this reviewed population was 50 years.

Diagnosis/testing.

The diagnosis of vEDS is based on clinical findings and confirmed by identification of a heterozygous pathogenic variant in COL3A1. DNA sequence analysis detects >95% of pathogenic variants, while rare exon deletions are detected by COL3A1 deletion/duplication analysis or collagen screening and cDNA amplification. Analysis of collagens produced by cultured fibroblasts ("biochemical studies") from affected individuals can demonstrate abnormalities of type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility in cells from some individuals in whom no pathogenic variant was detected by genomic sequencing.

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); arteriography should be used with great caution and 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 clinical evaluation and genetic testing.

Pregnancy management: Preconception counseling is important and pregnant women should be followed in a high-risk obstetric program.

Other: A MedicAlert® bracelet should be worn.

Genetic counseling.

vEDS 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. Both parental somatic/germline mosaicism and parental isolated germline mosaicism have been reported. Prenatal testing for pregnancies at increased risk is possible in families in which the pathogenic variant in COL3A1 has been identified. In rare families in which only the biochemical abnormality is known, analysis of cultured CVS cells can substitute.

Diagnosis

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. Clinical diagnostic criteria established in Villefrance in 1997 [Beighton et al 1998] 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 vermillion 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)
  • Gingival recession

Establishing the Diagnosis

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

  • Identification of a heterozygous COL3A1 pathogenic variant on molecular genetic testing (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 or a variant of uncertain significance is identified

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 testing approaches can include single-gene testing, use of a multi-gene panel, and genomic testing.

  • Single-gene testing. Sequence analysis of COL3A1 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes COL3A1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of vEDS. Such testing may include whole-exome sequencing (WES) or whole-genome sequencing (WGS).

    For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Vascular Ehlers-Danlos Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
COL3A1Sequence analysis 3>95% 4
Gene-targeted deletion/duplication analysis 5~1% 6
Unknown 7NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

The majority (~2/3) of identified pathogenic variants result in substitution of other amino acids for glycine residues in the Gly-X-Y triplets of the major triple helical domain. Most of the remaining pathogenic variants affect splice sites and usually result in exon skipping, but other more complex splice outcomes can occur. The majority of exon-skipping events have been confirmed by cDNA amplification and sequencing. About 4% of identified pathogenic variants lead to mRNA instability or to failure of chain association in the products of the mutant allele [Schwarze et al 2001, Leistritz et al 2011].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

The low frequency of genomic deletions is consistent with the failure to detect a deletion in 155 specimens submitted for COL3A1 sequence analysis [Author, personal experience; Collagen Diagnostic Laboratory]. One 3.5-Mb contiguous gene deletion that includes COL3A1 was identified by MLPA [Meienberg et al 2010].

7.

To date, locus heterogeneity has not been reported.

Test characteristics. See Clinical Utility Gene Card [Mayer et al 2013] for information on test characteristics including sensitivity and specificity.

Biochemical (protein-based) testing. Biochemical testing for vEDS requires cultured dermal fibroblasts. Proteins synthesized by these cells are biosynthetically labeled with radio-labeled proline, and assessed by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The amount of type III procollagen synthesized, the quantity secreted into the medium, and the electrophoretic mobility of the constituent chains are assessed.

Analysis of type III procollagen synthesized by cultured cells can identify abnormalities in synthesis and mobility of type III collagen chains. This testing is a valuable method used to determine if a unique sequence variant in COL3A1 results in protein alterations and to evaluate the outcome of splice site variants. In rare instances biochemical analysis may identify very small insertions or deletions – and perhaps inversions – not identified by arrays.

cDNA testing. Analysis of cDNA (synthesized from mRNA extracted from cultured fibroblasts) may identify the array of pathogenic splice products that result from a single splice site alteration or synonymous variants, or to characterize rare small multiexon deletions not detected by deletion/duplication analysis (e.g., MLPA).

Clinical Characteristics

Clinical Description

A retrospective review of the health history of more than 1200 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) as compared to 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 a French cohort of 215 individuals with vEDS, but the gender difference in mean survival was not found [Frank et al 2015].

Children

The majority (60%) of individuals with vEDS who are diagnosed prior to age 18 years are identified because of a positive family history. (See Evaluation of Relatives at Risk and Genetic Counseling for discussion of genetic testing of at-risk children to facilitate appropriate intervention in the occurrence of a major complication and implementation of risk-reducing behaviors.) Approximately 15% of these individuals had experienced a major complication of vEDS by the time of testing [Pepin et al 2014]. Of the 121 children tested in the absence of a positive family history, 65 presented with a major complication at an average age of 11 years. Four minor diagnostic features (distal joint hypermobility, easy bruising, thin skin, and clubfeet) were most often present in those ascertained without a major complication. At birth, clubfoot (unilateral or bilateral) is noted in 8% of children with vEDS. Hip dislocation, limb deficiency, and amniotic bands appeared in approximately 1% of affected infants. Death that occurred in the first two decades of life almost always resulted from spontaneous artery rupture or dissection. Arterial rupture, 60% of which involved the aorta, was responsible for all deaths in young males.

Adults

Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a missense or exon-skipping COL3A1 pathogenic variant. These complications are dramatic and often unexpected, presenting as sudden death, stroke and its neurologic sequelae, acute abdomen, retroperitoneal bleeding, uterine rupture at delivery, and/or shock. The average age for the first major arterial or gastrointestinal complication was 31 years in this reported group [Rana et al 2011].

Cardiovascular. Vascular complications include rupture, aneurysm, and/or dissection of major or minor arteries. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, or may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%). The clinical presentation depends on the location of the arterial event. Unexplained acute pain warrants immediate medical attention. Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection.

Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. Venous varicosities also occur.

Gastrointestinal. Perforation of the gastrointestinal (GI) tract occurs in approximately 15% of individuals with identified COL3A1 pathogenic variants, though seldom in individuals with null variants. The majority of GI perforations occur in the sigmoid colon. Ruptures of the small bowel and stomach have been reported, though infrequently. Iatrogenic perforation during colonoscopy has also been reported [Rana et al 2011]. Bowel rupture is rarely lethal (3%) [Pepin et al 2000], with most deaths reported as a result of unexpected hemorrhage or artery rupture during surgical repair.

Surgical intervention for bowel rupture is necessary and usually lifesaving. The successful surgical approach to perforation repair in vEDS includes partial colectomy, colostomy, and reversal after several months. Reports of primary repair are few.

Complications during and following surgery are related to tissue and vessel friability, which result in recurrent arterial or bowel tears, fistulae, poor wound healing, and suture dehiscence. Individuals who survive a first complication may experience recurrent rupture. The timing and site of repeat rupture cannot be predicted by the first event.

Pulmonary. Spontaneous and/or recurrent pneumothoraces may be the first significant presenting feature of vEDS. Hemothorax and hemopneumothorax have been reported, often in association with pulmonary blebs, cystic lesions, and hemorrhagic or fibrous nodules. Hemoptysis can be severe and recurrent, even life threatening [Hatake et al 2013]. Pathologic evaluation may demonstrate acute hematoma, fibrous nodules, vascular disruption, intraluminal and interstitial hemosiderosis, and emphysematous changes [Kawabata et al 2010]. Successful lung transplantation was reported in one individual with severe pulmonary complications of vEDS [García Sáez et al 2014].

Ocular. Keratoconus has been reported in vEDS [Kuming and Joffe 1977]. Carotid cavernous sinus fistulas typically present with sudden onset ocular symptoms including blurred vision, diplopia, ocular pain, proptosis, and chemosis.

Dental complications include periodontal disease and gingival recession. A more recent study characterized the gingival phenotype in vEDS as generalized thinness and translucency of the gingiva with increased fragility [Ferré et al 2012]. Disorders of the temporomandibular joint and defects in dentin formation are also more common in individuals with vEDS.

Other rare complications include rupture of the spleen or liver [Pepin et al 2000, Ng & Muiesan 2005]. Elastosis perforans serpiginosa is a rare but reported skin finding [Ahmadi & Choi 2011, Ferré et al 2012].

Pregnancy. In a retrospective review of 565 deliveries by 256 affected women, fatal complications occurred in 5.3%, a lower estimate than previously reported [Murray et al 2014]. A study of 35 affected women reported life-threatening complications in 15% of 76 deliveries including arterial dissection (9%), uterine rupture (3%), and surgical complications (3%). Approximately half of deliveries to women with vEDS were uncomplicated [Murray et al 2014].

Genotype-Phenotype Correlations

More than 600 unique COL3A1 pathogenic variants have been aggregated into the Ehlers Danlos Syndrome Variant Database. 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 1200 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 vEDS individuals identified with a pathogenic null alteration [Leistritz et al 2011].

Nomenclature

The following terms have been used to describe vEDS:

  • 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 1500 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]. This leads to a minimum estimate of the prevalence of about 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 non-vascular complications may not raise diagnostic suspicion of vEDS.

Differential Diagnosis

Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation who have normal collagen III biochemical studies or molecular analysis of COL3A1.

Table 2.

Disorders to Consider in the Differential Diagnosis of vEDS

Disease NameGene(s)MOIOverlapping Clinical FeaturesDistinguishing Clinical Features
Ehlers-Danlos syndrome, classic typeCOL5A1
COL5A2
COL1A1 1
AD
  • Typically not associated w/blood vessel, bowel, or organ rupture; however, mutation of COL1A1 has been reported in individuals w/classic EDS & aneurysm & dissection of large vessels 1
  • Soft, doughy, stretchy skin
  • Abnormal scars
  • Significant large-joint hypermobility
Ehlers-Danlos syndrome, kyphoscoliotic formPLOD1AR
  • Vascular rupture may be a feature
  • Progressive scoliosis
  • Hypotonia
  • Easy bruising & tissue fragility
  • Fragility of the globe
Ehlers-Danlos syndrome, periodontal form (OMIM 130080)Molecular basis unknownAD
  • Bruising & skin staining, particularly shins
  • Rare
  • Features of the classic type w/the additional findings of early periodontal friability
Isolated arterial aneurysmFootnote 2
  • Single arterial aneurysm or dissection
  • Usually NOT the result of a type III collagen defect
Loeys-Dietz syndromeTGFBR1 TGFBR2 SMAD3 TGFB2AD
  • Vascular findings (cerebral, thoracic, & abdominal arterial aneurysms and/or dissections)
  • Aggressive arterial aneurysms & high incidence of pregnancy-related complications
  • Skeletal manifestations
  • ~75% of affected individuals have craniofacial manifestations
  • ~25% of affected individuals have systemic manifestations but minimal or absent craniofacial features
Polycystic kidney disease, autosomal dominant (ADPKD)PKD1
PKD2
AD
  • ADPKD should be considered in individuals w/intracranial aneurysm
  • Vascular abnormalities include intracranial aneurysms, dilatation of the aortic root, & dissection of the thoracic aorta; mitral valve prolapse
  • Generally late-onset
  • Bilateral renal cysts & cysts in other organs
  • Abdominal wall hernias
  • Renal manifestations including hypertension, renal pain, & renal insufficiency
Marfan syndromeFBN1AD
  • Marfan syndrome should be considered if the presenting vascular complication is an aortic aneurysm or dissection.
  • vEDS & Marfan syndrome can be distinguished relatively easily on physical examination.
  • Individuals w/Marfan syndrome typically have dolichostenomelia & arachnodactyly, lens dislocation, & dilatation or aneurysm of only the aorta.
Gastrointestinal entities
  • Gastrointestinal entities to be considered in individuals of any age w/large or small bowel rupture are perforated diverticulitis, irritable bowel disease, or inflamed Meckel's diverticulum.
1.

A COL1A1 pathogenic variant p.Arg134Cys was identified in two unrelated children with classic EDS [Nuytinck et al 2000]. The same substitution was subsequently identified in three unrelated persons with aneurysms and rupture of medium-sized arteries in young adulthood. These individuals also had thin and hyperextensible skin, easy bruising, and abnormal wound healing [Malfait et al 2007; Malfait & De Paepe, personal observation]. Mutation of COL1A1, however, is not a major cause of classic EDS [Malfait et al 2005]. See EDS, Classic Type.

2.

Familial forms of arterial aneurysm have been linked to at least three different loci in addition to the six identified genes (see Thoracic Aortic Aneurysms and Aortic Dissections).

Management

Evaluations Following Initial Diagnosis

Currently, no consensus exists regarding the appropriate extent of evaluation at the time of initial diagnosis.

  • Approach to a vascular evaluation depends on the age of the individual and the circumstances in which the diagnosis is made. Because of the risk of asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken [Chu et al 2014]; the approach employed varies by geographic region and by institution (see Surveillance).
  • Because no specific gastrointestinal findings are known to precede or predict bowel rupture, there is no benefit from invasive GI evaluation.
  • Consultation with a medical geneticist and/or genetic counselor is appropriate.
  • Establishment of an organized care team including a primary care physician, vascular surgeon, general surgeon, and a geneticist may aid in emergency preparedness. In addition, individuals with vEDS should carry documentation of their genetic diagnosis, such as a MedicAlert® or emergency letter.

Treatment of Manifestations

Surgical intervention may be life-saving 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 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 between endovascular and open repair.

Prompt surgical intervention of bowel rupture is 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 colectomy to reduce the risk of recurrent bowel rupture. 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].

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

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, intervention is considered earlier and surveillance is seen to have greater benefit. There are, however, no published data that assess the efficacy of screening strategies to identify 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.

Blood pressure monitoring on a regular basis is recommended to allow for early treatment if hypertension develops, which will presumably reduce 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. 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 utilize genetic testing for colon cancer risk assessment (provided the genetic etiology of colon cancer has been established in an affected family member).

Elective surgery. Because tissue fragility results in a higher risk of surgical complications, elective surgery for individuals with vEDS is discouraged unless the benefit is expected to be substantial. In general, avoidance of surgery in favor of more conservative management is advised.

Evaluation of Relatives at Risk

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

  • Molecular genetic testing if the pathogenic variant in the family is known;
  • Clinical evaluation and physical examination 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

It is prudent to follow pregnant women with vEDS in a high-risk obstetrical program.

It is not known if elective caesarian section or pre-term delivery decreases the risk of mortality.

Educating the pregnant woman as to possible complications and the need for close monitoring is recommended.

Experience with use of assisted reproductive technologies for women with vEDS is limited [Bergeron et al 2014].

Therapies Under Investigation

A clinical trial of the efficacy of a cardioselective β-blocker with β-2 agonist vasodilatory properties (celiprolol) in reducing risk of arterial rupture or dissection concluded that there was a benefit: a reduced number of arterial events (rupture or dissection, fatal or not) was reported in the treatment group [Ong et al 2010]. Although the study was directed to measure benefit in individuals with vEDS, randomization to treatment or control group was undertaken prior to molecular testing. The treated and untreated groups with a confirmed pathogenic variant differed in size and age distribution; thus, it is difficult to determine if there is a measurable benefit. No further studies published to date have attempted to replicate the original findings.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 [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.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband and germline mosaicism in a parent. Two families in which there appears to be isolated germline mosaicism have been identified [Byers et al 2003, Palmeri et al 2003].
  • Parental somatic mosaicism is reported in about 15% of families studied in which the proband does not have an obviously affected parent [Author, personal experience]. 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.
  • 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 genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to each sib is 50%.
  • If the COL3A1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the risk to the sibs is about 1% because of the possibility of germline mosaicism.

Offspring of a proband

  • Each child of an individual with vEDS has a 50% chance of inheriting the COL3A1 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.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, 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 apparent de novo pathogenic variant. When neither parent of a proband with vEDS has the pathogenic variant or clinical evidence of the disorder, the COL3A1 pathogenic variant is likely de novo. However, possible non-medical explanations that can be explored include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 COL3A1 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 [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 often 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].

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

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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the COL3A1 pathogenic variant has been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk for vEDS may be options that a couple may wish to consider.

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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association Francaise des Syndrome d'Ehlers Danlos
    34 rue Léon Joulin
    Turns 37 000
    France
    Email: contact@afsed.com
  • Ehlers-Danlos National Foundation
    1760 Old Meadow Road
    Suite 500
    McLean VA 22102
    Phone: 703-506-2892
    Email: ednfstaff@ednf.org
  • Ehlers-Danlos Support Group
    PO Box 337
    Aldershot Surrey GU12 6WZ
    United Kingdom
    Phone: 01252 690940
    Email: director@ehlers-danlos.org
  • Ehlers-Danlos Syndrome Network C.A.R.E.S. Foundation
    PO Box 66
    Muskego WI 53150
    Phone: 262-514-2851
    Email: EDSLynnCARES@gmail.com
  • National Library of Medicine Genetics Home Reference
  • Medline Plus
  • National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)
    Phone: 800-334-8571 ext 24640
    Email: gentac-registry@rti.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Vascular Ehlers-Danlos Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Vascular Ehlers-Danlos Syndrome (View All in OMIM)

120180COLLAGEN, TYPE III, ALPHA-1; COL3A1
130050EHLERS-DANLOS SYNDROME, TYPE IV, AUTOSOMAL DOMINANT

Gene structure. The COL3A1 cDNA comprises 51 exons distributed over 44 kb of genomic DNA (reference sequence NM_000090.3). For a detailed summary of gene and protein information, see Table A, Gene.

Note on gene and protein nomenclature. For fibrillar collagen genes of the same clade (COL1A1, COL1A2, COL2A1, COL3A1, and COL5A2) there is a "legacy" naming system so that all genes have 52 exons – derived from the structure of COL1A2. In the case of COL3A1, there is fusion of two exons that are equivalent to exons 4 and 5 in COL1A2 and the fusion exon is called exon 4/5. In addition, there is a second "legacy" protein naming system in which, in addition to the use of the p.1Met nomenclature, there is a system in which the first glycine of the canonic triple helical domain is referred to as residue 1 in the triple helix. In reports from some laboratories, both systems are used and the difference in protein position between the two systems is indicated. In older reports from some laboratories, the legacy description for protein may be used in combination with the standard description for nucleotide position, leading to considerable confusion.

Benign allelic variants. The Database of Human Type I and Type III Collagen Mutations provides a list of known variants.

Pathogenic allelic variants. More than 600 allelic variants in COL3A1 that result in a disease-causing phenotype have been identified.

The majority of identified pathogenic variants result in single amino-acid substitutions for glycine in the Gly-X-Y repeat of the triple helical region of the type III procollagen molecule. About a quarter of the known variants occur at splice sites, and most result in exon skipping. A smaller number of splice site variants lead to the use of cryptic splice sites with partial-exon exclusion or intron inclusion. The vast majority of exon-skipping splice site variants have been identified at the 5' donor site, with very few found at the 3' splice site.

Several partial-gene deletions have been reported as well. Less common are variants that create new termination codons and result in COL3A1 haploinsufficiency ("null" pathogenic variants) [Schwarze et al 2001, Leistritz et al 2011]. The consequence is synthesis of about one half the amount of normal type III procollagen. (See Database of Human Type I and Type III Collagen Mutations.)

In the analysis to date of the pathogenic variants identified in COL3A1, at least two classes of variants – substitutions of glycine in the triple helical domain by alanine and null variants – are underrepresented (in terms of the predicted frequency) among individuals with clinical features of vEDS. Thus, some pathogenic variants in COL3A1 may not produce a typical vEDS clinical picture. It is unclear if individuals with these classes of pathogenic variants have attenuated or subclinical phenotypes and present at later ages or if there is a molecular explanation for the absence of certain pathogenic variant types.

Normal gene product. COL3A1 encodes the proα1(III) chain of type III procollagen, a major structural component of skin, blood vessels, and hollow organs. The type III procollagen molecule is a homotrimer, with constituent chains 1,466 amino acids in length.

Abnormal gene product. Pathogenic variants in COL3A1 typically result in a structural alteration of type III collagen that leads to intracellular storage and impaired secretion of collagen chains. Production of half the normal amount of type III procollagen occurs in a minority of individuals.

References

Published Guidelines/Consensus Statements

  1. 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 11-17-15. [PubMed: 23428972]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 11-17-15.

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Chapter Notes

Revision History

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