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Ehlers-Danlos Syndrome, Vascular Type

[Acrogeria; EDS Type IV; Ehlers-Danlos Syndrome Type IV; Ehlers-Danlos Syndrome, Arterial-Ecchymotic Type; Sack-Barabas Syndrome]

Summary

Disease characteristics.  Ehlers-Danlos syndrome, vascular type (also known as EDS IV) is characterized by thin, translucent skin; easy bruising;characteristic facial appearance; and arterial, intestinal and/or uterine fragility. Affected individuals are at risk for arterial rupture, aneurysm, and/or dissection; gastrointestinal perforation or rupture; and uterine rupture during pregnancy. One fourth of individuals with EDS, vascular type, experience a significant medical problem by age 20 years and more than 80% by age 40 years. The median age of death is 48 years.

Diagnosis/testing.   The diagnosis of EDS, vascular type, is based on compatible clinical findings and confirmed by biochemical testing. Biochemical studies in affected individuals demonstrate abnormal electrophoretic mobility and abnormal efficiency of secretion of type III procollagen in cultured dermal fibroblasts. Molecular genetic testing to identify mutations in the COL3A1 gene (chromosomal locus 2q31) is available for genetic counseling purposes to individuals with the biochemically confirmed diagnosis of EDS, vascular type.

Genetic counseling.   The vascular type of EDS is inherited in an autosomal dominant manner. About 50% of affected individuals have inherited the mutant COL3A1 gene from an affected parent and about 50% have new disease-causing mutations. Offspring of an affected individual have a 50% chance of inheriting the disease-causing allele. Parental somatic mosaicism for COL3A1 mutations has been documented in several families in which two affected individuals have been born to unaffected parents. Prenatal testing is possible for fetuses at 50% risk in families in which the underlying biochemical abnormality of type III collagen or disease-causing mutation in COL3A1 has been identified.

Diagnosis

The diagnosis of Ehlers-Danlos syndrome, vascular type, also known as EDS type IV, is suspected on the basis of clinical findings and a family history consistent with autosomal dominant inheritance; however, in most instances, biochemical testing by protein electrophoresis of collagens synthesized by cultured fibroblasts is required for definitive diagnosis. Molecular genetic testing to identify mutations in the COL3A1 gene (chromosomal locus 2q31) is available for genetic counseling purposes to individuals with the biochemically confirmed diagnosis of the vascular type of EDS.

Clinical Diagnosis

Diagnostic criteria and standardized nomenclature for the Ehlers-Danlos syndromes were developed by a medical advisory group in a conference sponsored by the Ehlers-Danlos Foundation (USA) and the Ehlers-Danlos Support Group (UK) at Villefranche in 1997 [Beighton et al 1998] and modified here to reflect the author's experience. The combination of any two of the criteria now listed as major diagnostic criteria should have a high specificity for EDS, vascular type IV; biochemical testing is strongly recommended to confirm the diagnosis.

The presence of one or more minor criteria contribute to the diagnosis of the vascular type of EDS, but are not sufficient to establish the diagnosis.

Major diagnostic criteria for the vascular type of EDS include:

• Arterial rupture
• Intestinal rupture
• Uterine rupture during pregnancy
• Family history of the vascular type of EDS

Minor diagnostic criteria for the vascular type of EDS include:

• Thin, translucent skin (especially noticeable on the chest/abdomen)
• Easy bruising (spontaneous or with minimal trauma)
• Characteristic facial appearance (thin lips and philtrum, small chin, thin nose, large eyes)
• Acrogeria (an aged appearance to the extremities, particularly the hands)
• Hypermobility of small joints
• Tendon/muscle rupture
• Early-onset varicose veins
• Arteriovenous carotid-cavernous sinus fistula
• Pneumothorax/pneumohemothorax
• Chronic joint subluxations/dislocations
• Congenital dislocation of the hips
• Talipes equinovarus (clubfoot)
• Gingival recession

Testing

Biochemical testing.  Biochemical testing for the vascular type of EDS requires cultured dermal fibroblasts. Proteins synthesized by these cells are labeled with radioactive-labeled proline and the proteins synthesized by the cells are 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. Cells from individuals with the vascular type of EDS have abnormalities of type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility [Pope et al 1975 , Pope et al 1988]. Biochemical testing for the vascular type of EDS probably identifies more than 95% of individuals with structural alterations in the proteins synthesized. False positive results are rare [Pepin, unpublished]. A variety of EDS, vascular type, in which production of normal type III procollagen is reduced to half-normal levels, has been recognized recently. This variety results from heterozygosity for mutations that result in either loss of the products of one allele or failure of the protein to assemble into molecules [Schwarze et al 2001].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.

Molecular genetic testing of the vascular type of EDS relies upon the collagen biochemical testing to identify likely regions to search for specific disease-causing mutations in the COL3A1 gene (chromosomal locus 2q31). Molecular genetic testing is available for genetic counseling purposes to individuals with the biochemically confirmed diagnosis of vascular type EDS.

To date, more than 250 COL3A1 disease-causing mutations have been identified, with fewer than a dozen recurrent mutations. COL3A1 mutations identified in individuals with the vascular type of EDS include point mutations that result in substitutions for glycine in the triple helical region of the collagen molecule; splice site mutations that result in exon skipping, intron inclusion, or complex and multiple outcomes; partial gene deletions; and, less commonly, mutations that result in haploinsufficiency. The vast majority of exon-skipping splice site mutations have been identified at the 5' donor site with very few 3' splice site mutations identified [Schwarze et al 1997]. Point mutations that create new chain termination codons and result in COL3A1 haploinsufficiency ("null" mutations) have more recently been described in families with EDS vascular type IV [Schwarze et al 2001].

Genetically Related Disorders

To date, no other diseases are known to be caused by mutations in the COL3A1 gene.

• EDS III.  A single report of a family with clinical features of familial hypermobility syndrome (EDS III) and a COL3A1 mutation typically associated with the vascular type of EDS (G637S) [Narcisi et al 1994] led to the suspicion of a causative relationship between COL3A1 mutations and EDS III; however, biochemical studies of collagen synthesis have not identified a type III collagen defect in other families with EDS III. Given the relatively young ages of most individuals in the reported family and sparse history, reassessment is warranted.

• Familial aortic aneurysm.  A COL3A1 glycine substitution mutation has been identified in one family with familial aortic aneurysm [Kontusaari, Tromp, Kuivaniemi, Ladda et al 1990] and in another family with aortic aneurysm [Kontusaari, Tromp, Kuivaniemi, Romanic et al 1990]. One of the reported families likely had the vascular type of EDS that had gone undetected prior to identification of the mutation. It is possible that the second family with aortic aneurysm represents the milder end of a clinical spectrum caused by mutations in the COL3A1 gene. However, studies of other families with familial and non-familial aneurysm have revealed no evidence of causative type III collagen mutations [Kuivaniemi et al 1993 , Tromp et al 1993].

Clinical Description

A retrospective review of the health history of more than 400 individuals with the vascular type of EDS confirmed by biochemical and/or molecular genetic testing has delineated the natural history of the disorder. Among individuals ascertained as a result of complications, 25% had experienced a significant medical complication by age 20 years and more than 80% by age 40 years. In a population ascertained on the basis of major complications or clinical criteria alone, in which all had evidence of abnormal type III procollagen production in cultured dermal fibroblasts, the median age of death is 48 years [Pepin et al 2000].

About 12% of neonates with the vascular type of EDS have clubfoot and 3% have congenital dislocation of the hips. In childhood, inguinal hernia, pneumothorax, and recurrent joint dislocation or subluxation are common [Pepin et al 1992]. Patients have a lifelong history of easy bruising. Keratoconus [Kuming et al 1977], periodontal disease, and venous varicosities have been reported [Tsipouras et al 1986]. Many children with the vascular type of EDS have few complications and, in families with negative family history, the disease is often unrecognized in childhood.

Vascular complications and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with the vascular type of EDS. Such complications are dramatic and unexpected, often presenting as sudden death, stroke and its neurological sequelae, acute abdomen, retroperitoneal bleeding, uterine rupture at delivery, and/or shock. The average age for the first major arterial or gastrointestinal complication is 23 years. Vascular complications include rupture, aneurysm, and/or dissection of major or minor arteries. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (50%), head and neck (25%), and extremities (25%). Although uncommon, the vascular type of EDS is a cause of stroke in young adults. The mean age of intracranial aneurysmal rupture, spontaneous carotid-cavernous sinus fistula, and cervical artery aneurysm is 28 years [North et al 1995]. Rupture of the gastrointestinal tract occurs in about 25% of affected individuals. The majority of GI perforations occur in the sigmoid colon. Rupture of the small bowel and stomach have been reported, though infrequently. Bowel rupture is usually not lethal (3%) [Pepin et al 2000]. Recurrent bowel rupture proximal to the first sigmoid tear is common. Complications resulting from tissue fragility often delay recovery from surgery.

Surgical intervention for bowel rupture is necessary and usually lifesaving. 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.

Pregnancy for women with the vascular type of EDS has as much as a 12% risk for death from peripartum arterial rupture or uterine rupture [Rudd et al 1983 ; Peaceman et al 1987 ; Pepin et al 2000].

Genotype-Phenotype Correlations

• The phenotypic effects of COL3A1 null mutations appear to be identical to glycine substitution mutations and exon-skipping mutations, although the onset of first symptoms may be relatively delayed. The number of families described with COL3A1 null mutations are small [Schwarze et al 2001].
• A possible relationship exists between the acrogeroid phenotype and mutations that alter sequences in the carboxyl-terminal end of the type III collagen triple helix [Johnson et al 1995].
• Somatic mosaicism for COL3A1 mutations is rarely associated with symptoms. In two individuals with mosaicism for a mutation in the COL3A1 gene who had complications of EDS, vascular type, the distribution and extent of the mosaicism is under investigation [Pepin et al, personal observation].

Prevalence

Estimates of the prevalence of the vascular type of EDS vary from 1: 50,000 to 1: 100,000 [Byers et al 1995]. Because many families with the vascular type of EDS are identified only after a severe complication or death, it is likely that individuals/families with COL3A1 mutations with a mild phenotype do not come to medical attention and therefore go undetected.

Differential Diagnosis

Other forms of Ehlers-Danlos syndrome should be considered in patients with easy bruising, joint hypermobility, and/or chronic joint dislocation who have normal collagen III biochemical studies. The disorders in which clinical findings overlap with the vascular type of EDS include the following:

• Ehlers-Danlos syndrome, classic type is distinguished by soft, doughy, stretchy skin, abnormal scars, and significant large joint hypermobility without accompanying blood vessel, bowel, or organ rupture.

• Ehlers-Danlos syndrome VI (kyphoscoliotic form) is characterized by easy bruising and tissue fragility, progressive scoliosis, hypotonia, and fragility of the globe. Vascular rupture may be a feature of this type of EDS.

• Ehlers-Danlos syndrome VIII (periodontal form) is a rare connective tissue disorder including features of the classic type and the vascular type, but with the additional findings of early periodontal friability. It is uncertain if EDS VIII represents a distinct entity.

• Isolated arterial aneurysm is usually not the result of a type III collagen defect. Other causes of arterial rupture include localized trauma and collagen vascular disease.

• Polycystic kidney disease, autosomal dominant should be considered in individuals with intracranial aneurysm.

• Marfan syndrome should be considered if the presenting vascular complication is an aortic aneurysm. The vascular type of EDS and Marfan syndrome can be distinguished relatively easily on physical examination. Individuals with Marfan syndrome typically have dolichostenomelia and arachnodactyly, lens dislocation, and dilatation or aneurysm of the aorta only.

• Gastrointestinal entities to be considered in patients of any age with large or small bowel rupture are perforated diverticulitis, irritable bowel disease, or inflamed Meckel's diverticulum. Isolated gastrointestinal bleeding, such as seen in pseudoxanthoma elasticum and hereditary hemorrhagictelangectasia , are not part of the usual presentation of EDS vascular type.

Management

Confirmation of the diagnosis of the vascular type of EDS is likely to prolong life and improve quality of life for affected individuals through better understanding of potential complications and avoidance of high-risk activities. Because of inherent tissue fragility, it is prudent for individuals with the vascular type of EDS to minimize the risk of trauma by avoiding collision sports (e.g., football), heavy lifting, and weight training. No evidence exists that moderate recreational exercise is detrimental. No measures to prevent arterial vessel tears are known.

Because the risk of surgical complications is increased due to increased tissue fragility, elective surgery for individuals with the vascular type of EDS is discouraged. When surgery is required for the treatment of arterial or bowel complications or other health problems, it is appropriate to minimize surgical exploration and intervention. In general, avoidance of surgery in favor of more conservative management is advised. For example, bleeding from a small vessel into a confined space is often best treated conservatively. In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of the vascular type of EDS and its associated tissue fragility.

Screening adults with the vascular type of EDS for sites of arterial aneurysm by MRI or ultrasonography has been discussed in the literature from time to time. If such surveillance is undertaken, arteriograms are not recommended as arterial tear/dissection may result at the site of entry of the catheter; the pressure required for insertion of the catheter can lead to arterial rupture. Preferable modes of surveillance include venous subtraction angiography and MRI or CT scan without contrast material. As arterial rupture in individuals with the vascular type of EDS is not always preceded by aneurysm, the necessity for periodic arterial screening is questionable. Instructing the patient to seek immediate medical attention for unexplained pain and to wear a Medic Alert ^® bracelet is recommended.

Prompt surgical intervention of bowel rupture is crucial. Bowel continuity can be restored successfully in most instances. The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend distal colectomy to reduce the risk for recurrent bowel rupture. Some physicians and patients consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [Freeman et al 1996].

It is prudent to follow patients with the vascular type of EDS who are pregnant in a high-risk obstetrical program. It is not known if elective caesarian section decreases the risk of mortality without increasing morbidity. Educating the patient as to possible complications and the need for close monitoring and attention to sudden unexplained pain is recommended.

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 or cultural issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The vascular type of EDS is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband.  About 50% of affected individuals have inherited the mutant COL3A1 gene from an affected parent, and about 50% of affected individuals have a new disease-causing mutation. It is important to note that parental somatic mosaicism for COL3A1 mutations has been documented in several families in which two affected individuals have been born to unaffected parents [Kontusaari et al 1992].

Sibs of a proband.  The risk to the sibs depends upon the genetic status of the parent. If the parent is affected, the risk to each offspring is 50%. If the parent is unaffected clinically, there is a small risk that the parent has either somatic mosaicism or germline mosaicism for a COL3A1 mutation, making the risk of having a second affected child low, probably between 1% and 5% [Pepin et al, unpublished].

Offspring of a proband.   An affected individual has a 50% risk of transmitting the disease-causing mutation to each offspring.

Other family members of a proband.  The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation.  When the parents of a proband with an autosomal dominant condition are genetically unaffected, possible non-medical explanations include alternate paternity or undisclosed adoption.

Testing of at-risk asymptomatic children.  The idea of testing apparently asymptomatic children for disorders that have most of the complications in adult life raises ethical considerations. Consensus holds that children at risk for adult-onset disorders should not have testing in the absence of symptoms if there are no positive consequences of testing, such as intervention or improved surveillance.The principal arguments against testing children who do not have symptoms are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications [Bloch & Hayden 1990 , Harper & Clarke 1990]. In the case of the vascular form of EDS, the benefits of testing include elimination of concern for those children who do not have the COL3A1 mutant allele identified in the affected parent, and for those with the mutant allele, improved surveillance, awareness of treatment for potential complications, and appropriate restriction of high-impact sports.

Prenatal Testing

Prenatal diagnosis is possible for fetuses at 50% risk in families in whom the underlying biochemical abnormality of type III collagen or disease-causing mutation of COL3A1 has been identified. If only the biochemical defect in type III collagen is known (see Biochemical Testing), prenatal diagnosis using the biochemical assay can only be performed on cultured cells obtained by chorionic villus sampling (CVS) at 10-12 weeks' gestation*. If the underlying COL3A1 disease-causing mutation is known, DNA extracted from fetal cells obtained by CVS at 10-12 weeks' gestation or amniocentesis at 16-18 weeks' gestation can be analyzed using the techniques described in Molecular Genetic Testing .

*Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular Genetics

Table 2. Molecular Genetics of Ehlers-Danlos Syndrome, Vascular Type

Gene	Locus	Product	Genomic Databases
COL3A1	2q31	Type III collagen chains

• Normal allelic variants: The COL3A1 cDNA comprises 51 exons distributed over 44 kb of genomic DNA.
• Pathologic allelic variants: Over 250 mutations in the COL3A1 gene that result in a disease-causing phenotype have been identified. The mutations described are point mutations (often single amino acid substitutions for glycine in the GLY-X-Y repeat of the triple helical region of the type III collagen molecule) and an equal number of exon- skipping mutations, including mutations at intron-exon boundaries that lead to the use of cryptic splice sites or exclusion of exons in the mRNA product. The vast majority of identified splice site mutations are located at the 5' exon boundary. Several gene deletions have been reported as well. COL3A1 null alleles are also known to produce the phenotype; a variety of mechanisms lead to nonsense-mediated decay of the mutation-bearing mRNA or to failure of chains to associate. The consequence is synthesis of about half the amount of normal type III procollagen. (See collagen database of human type I and type III collagen mutations.)
• Normal gene product: Collagen alpha 1 (III) chain (type III collagen chains). The COL3A1 gene encodes the chains of type III collagen, a major structural component of skin, blood vessels, and hollow organs. The type III collagen molecule is a homotrimer, a protein of 1,467 amino acids in length.
• Abnormal gene product: Mutations of the COL3A1 gene typically result in a structural alteration of type III collagen that leads to intracellular storage and impaired secretion of collagen chains.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

• Ehlers-Danlos National Foundation
  6399 Wilshire Blvd, Suite 200
  Los Angeles, CA 90048
  Phone:   323-651-3038; 800-956-2902
  Fax:  323-651-1366
  Email:   staff@ednf.org
  http://www.ednf.org/
  

• Canadian Ehlers-Danlos Association
  99 Cunningham Road
  Maple, Ontario
  L6A 2C2 Canada
  Phone:  416-334-2102
  Email:  office@ceda.ca
  http://www.ceda.ca/
  

• Ehlers-Danlos Support Group
  PO Box 335 Farnham
  Surrey, GU10 1XJ
  United Kingdom
  Phone:   +44 1252 690 940
  Email:   director@ehlers-danlos.org
  http://www.ehlers-danlos.org/
  

• Online Resource
  www.familyvillage.wisc.edu/lib_e-ds.htm
  

References

Articles on Ehlers-Danlos Syndrome

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Literature Cited

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