Clinical Diagnosis

Diagnostic criteria and standardized nomenclature for the Ehlers-Danlos syndromes (EDSs) were suggested by a medical advisory group in a conference sponsored by the Ehlers-Danlos National Foundation (US) and the Ehlers-Danlos Support Group (UK) at Villefranche in 1997 [Beighton et al 1998].

Diagnostic criteria for Ehlers-Danlos syndrome type IV (EDS type IV) are modified here to reflect the authors' experience.

The combination of any two of the major diagnostic criteria should have a high specificity for EDS type IV; DNA testing is strongly recommended to confirm the diagnosis. The presence of two or more minor criteria should lead to consideration of the diagnosis of EDS type IV but is not sufficient to establish the diagnosis.

Major diagnostic criteria for EDS type IV include:

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

Minor diagnostic criteria for EDS type IV include:

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

Testing

Biochemical (protein-based) testing. Biochemical testing for EDS type IV 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. Such testing remains a valuable resource to confirm mRNA and protein consequences when a unique sequence variant is identified and to look for protein abnormalities in an individual with convincing phenotype but an apparently normal sequence of COL3A1. Rare small multiexonic deletions not detected by deletion/duplication analysis (e.g., MLPA) may be identified using cDNA sequencing.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Sequence analysis of COL3A1 confirms the clinical diagnosis of EDS type IV over 95% of the time. Sequence analysis identifies variants of unknown significance, the role of which may be defined by biochemical (protein-based) testing.
• Deletion/duplication analysis. If a mutation is not detected on sequence analysis of genomic DNA, deletion/duplication analysis may be indicated, particularly in instances when sequencing does not identify heterozygous sequence variants and the phenotype is compelling. To date, such deletions are rare (<2%) in COL3A1.
• Biochemical (protein-based) testing. Testing of type III procollagen synthesized by cultured cells from a skin biopsy is the recommended assay when a mutation is not identified by sequence analysis or when a sequence variant of unknown clinical significance is found. Such testing may confirm mRNA and protein consequences of a variant of unknown significance or may identify a type III collagen protein abnormality, indicating that the mutation was missed as a result of a technical problem (e.g., mutation is masked by location under a primer or presence of a multiexonic deletion).

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Ehlers-Danlos syndrome, hypermobility type (EDS type III). A single report of a family with clinical features of EDS type III and a COL3A1 mutation typically associated with the EDS type IV (NM_000090.3:c.2410G>A (p.Gly804Ser) or Gly637Ser in the triple helical domain) [Narcisi et al 1994] led to the suspicion of a causative relationship between COL3A1 mutations and EDS type III; however, neither biochemical studies of collagen synthesis nor COL3A1 genomic DNA sequence analysis have identified a type III collagen defect in any other individuals with the clinical diagnosis of EDS type 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 was identified in one family described with familial aortic aneurysm, but clinically more consistent with EDS type IV, and in another family with aortic aneurysm. In spite of this report, existence of a subset of individuals with a COL3A1 mutation giving rise to the phenotype of familial aortic aneurysm in the absence of other findings of EDS type IV seems unlikely [Author, personal observation].

Natural History

A retrospective review of the health history of more than 400 individuals with Ehlers-Danlos syndrome (EDS) type IV confirmed by biochemical and/or molecular genetic testing delineated the natural history of the disorder [Pepin et al 2000]. 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.

As of 2010, more than 500 COL3A1 mutations have been identified by molecular testing in the authors’ laboratory and almost 200 others have been reported. Within this group a subpopulation of 3%-4% have haploinsufficiency mutations. Review of clinical histories of the COL3A1 probands and family members reveals a 15-year delay in onset of complications, similarly improved life expectancy, and paucity of both obstetric and bowel complications [Leistritz et al 2010].

Children. Approximately 12% of neonates with EDS type IV have clubfoot, and 3% have congenital dislocation of the hips. Rare infants have evidence of amniotic bands including a small number with limb deficiencies.

In childhood, inguinal hernia, pneumothorax, and recurrent joint dislocation or subluxation are described.

Affected individuals often have a lifelong history of easy bruising.

Most children with EDS type IV have few major complications; and, in families with a negative family history, the disorder is often unrecognized in childhood.

Adults. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with missense and exon-skipping mutations of COL3A1. Such 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 is 23 years in this group.

Individuals with haploinsufficiency mutations may present with arterial events (none yet are described with bowel-or pregnancy-related catastrophes); the average age of first event in this group is 37 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, or may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (50%), head and neck (25%), and extremities (25%). The clinical presentation depends on the location of the arterial event.

Rupture of the gastrointestinal (GI) tract occurs in about 25% of affected individuals with missense mutations. To date, such GI events have not been documented in the families with haploinsufficiency mutations. The majority of GI perforations occur in the sigmoid colon. Ruptures of the small bowel and stomach have been reported, though infrequently. Bowel rupture is rarely lethal (3%) [Pepin et al 2000]. Recurrent bowel rupture proximal to the first sigmoid tear is common.

Surgical intervention for bowel rupture is necessary and usually lifesaving. Surgical re-anastomosis can generally be accomplished. 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.

Rare complications include organ rupture that may involve the heart (with ventricular rupture), the spleen, or the liver [Pepin et al 2000, Ng & Muiesan 2005].

Keratoconus [Kuming & Joffe 1977], periodontal disease, and venous varicosities have been reported [Tsipouras et al 1986].

Pregnancy for women with EDS type IV has as much as a 12% risk for death from peripartum arterial rupture or uterine rupture [Pepin et al 2000].

Genotype-Phenotype Correlations

To date, the only clear genotype-phenotype correlations are the 15-year delay in onset of complications, decreased penetrance, and increased life expectancy in individuals with haploinsufficiency mutations, and the higher frequency of acrogeria in individuals with mutations that alter the carboxyl-terminal quarter of the triple helical domain of the chains of type III procollagen [Leistritz et al 2010].

Penetrance

In families identified on the basis of clinical complications, penetrance of the EDS type IV phenotype appears to be close to 100% with a missense or exon-skipping mutation; the age at which the mutation becomes penetrant may vary.

Nomenclature

The following terms have been used to describe EDS type IV:

• Status dysvascularis was introduced by Sack [1936]; never used extensively.
• Familial acrogeria, used by Gottron [1940], probably included some individuals with EDS type IV.
• 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.
• Ehlers-Danlos syndrome, vascular type came into widespread use following the shift from a numerical classification of EDS to a descriptive one [Beighton et al 1998].

Prevalence

There are no good current estimates of the prevalence of EDS type IV 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 mutations suggests that the overall prevalence of individuals with mutations in COL3A1 (see Molecular Genetics) could approach that of individuals with mutations in COL1A1, which is estimated to be close to 1:50,000.

Because many families with EDS type IV 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. In addition, because of the perceived rarity of the disorder, it is rarely considered and non-vascular complications rarely raise diagnostic suspicion of EDS type IV.

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; the approach employed varies by region and by institution (see Surveillance).

No gastrointestinal factors are known to increase the risk of bowel rupture, thus negating the need for initial invasive GI evaluation.

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 EDS type IV and its associated tissue fragility.

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.

A MedicAlert^® bracelet should be worn.

Surveillance

The use of surveillance of the arterial tree 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 alternative, 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, the noninvasive imaging such as sonography, MR or CT angiography with or without venous contrast has been documented to identify aneurysms, dissections, and vascular ruptures.

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.

Agents/Circumstances to Avoid

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

Elective surgery. Increased tissue fragility results in a higher risk of surgical complications; thus, elective surgery for individuals with EDS type IV is discouraged. 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.

Arteriograms. Because arterial tear/dissection may result at the site of entry of the catheter and at sites of high pressure injection, arteriograms are not recommended and the use of CTA, MRA, and ultrasonography should be considered for routine surveillance.

Routine colonoscopy should be avoided because of the risks of bowel perforation by the instrument and secondary to insufflation. Routine colonoscopy for cancer screening should be replaced with noninvasive measures. Virtual colonoscopy, which also involves insufflation, may have similar complications. In the face of a family history of cancer, standard or emerging strategies of surveillance may be of benefit.

Evaluation of Relatives at Risk

The genetic status of at-risk relatives can be clarified by molecular genetic testing if the disease-causing mutation in the family is known. For those found to have the family-specific mutation, management is the same as for individuals identified through clinical findings.

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 EDS type IV in a high-risk obstetrical program.

It is not known if elective caesarian section decreases the risk of mortality and vaginal and cervical tears and these benefits outweigh the associated morbidity.

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

Therapies Under Investigation

A recently published 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. Although the study was directed to measure benefit in individuals with EDS type IV, randomization to treatment or control group was undertaken prior to mutation characterization. The treated and untreated groups with mutations differed in size and age distribution so that it is difficult to determine if there is a measurable benefit [Ong et al 2010].

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

Mode of Inheritance

Ehlers-Danlos syndrome (EDS) type IV is an autosomal dominantly inherited disorder but almost half of the newly ascertained affected individuals have new mutations.

Risk to Family Members

Parents of a proband

• About 50% of affected individuals have inherited the COL3A1 mutation from an affected parent, and about 50% of affected individuals have a de novo disease-causing mutation.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination and molecular genetic testing as the rate of parental mosaicism in families with EDS type IV may be as high as 20%.
• Parental somatic mosaicism for COL3A1 mutations that includes the germline has been documented in 11 families in which affected individuals have been born to unaffected parents; mosaicism that is apparently limited to the germline has been reported in two families [Byers et al 2003, Palmeri et al 2003].

Note: Although many individuals diagnosed with EDS type IV have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or later onset of the disease in the affected parent.

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 parents are clinically unaffected and the proband's disease-causing mutation cannot be detected in DNA extracted from the leukocytes of either parent, there remains a chance that one parent is mosaic in his or her germline. In this situation the recurrence risk is probably about 1%.

Offspring of a proband. Each child of an individual with EDS type IV has a 50% chance of inheriting the mutation and developing the disorder.

Other family members of a proband. 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 are 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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 at-risk asymptomatic individuals younger than age 18 years. In the case of EDS type IV the benefits of testing individuals younger than age 18 years include: (1) elimination of concern for those children who do not have the COL3A1 mutant allele identified; and (2) improved surveillance, awareness of treatment for potential complications, and appropriate restriction of high-impact sports for those with the mutant allele.

Testing of apparently asymptomatic individuals younger than age 18 years for disorders in which most of the complications occur in adulthood raises ethical considerations. Consensus holds that individuals at risk for adult-onset disorders should not be tested during childhood in the absence of symptoms, if the testing can have no positive consequences such as intervention or improved surveillance. The principal arguments against testing asymptomatic individuals who are younger than age 18 years 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. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. In the authors’ experience the majority of families choose to test, even after discussion of the considerations mentioned above [Authors, personal experience].

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

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

Biochemical testing. Prenatal diagnosis is possible for pregnancies at increased risk in families in which the underlying biochemical abnormality of type III collagen has been identified. Prenatal diagnosis using the biochemical assay can be performed only on cultured cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. In most instances molecular genetic testing is preferable, more rapid, and available for a wider range of mutations.

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

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Published Guidelines/Consensus Statements

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 7-12-12. [PMC free article: PMC1801355] [PubMed: 7485175]
2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 7-12-12.

Literature Cited

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2. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77:31–7. [PubMed: 9557891]
3. Byers PH, Pepin MG, Schwarze U, Gaulke LK. Recurrence risk and asymptomatic and symptomatic mosaicism in Ehlers-Danlos syndrome (EDS) type IV. Am J Hum Genet. 2003;73S:206.
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6. Leistritz DF, Pepin MG, Schwarze U, Byers PH. COL3A1 haploinsufficiency results in EDS type IV with delayed onset of complications and longer life span when compared to missense and splice-site mutations. Poster session 1670. Washington, DC: American Society of Human Genetics 60^th Annual Meeting. 2010.
7. Meienberg J, Rohrbach M, Neuenschwander S, Spanaus K, Giunta C, Alonso S, Arnold E, Henggeler C, Regenass S, Patrignani A, Azzarello-Burri S, Steiner B, Nygren AO, Carrel T, Steinmann B, Mátyás G.(2010) Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency. Eur J Hum Genet. Dec;18(12):1315-21. [PMC free article: PMC3002852] [PubMed: 20648054]
8. Narcisi P, Richards AJ, Ferguson SD, Pope FM. A family with Ehlers-Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen. Hum Mol Genet. 1994;3:1617–20. [PubMed: 7833919]
9. Ng SC, Muiesan P. Spontaneous liver rupture in Ehlers-Danlos syndrome type IV. J R Soc Med. 2005;98:320–2. [PMC free article: PMC1168920] [PubMed: 15994597]
10. Oderich GS, Panneton JM, Bower TC, Lindor NM, Cherry KJ, Noel AA, Kalra M, Sullivan T, Gloviczki P. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg. 2005;42:98–106. [PubMed: 16012458]
11. Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J, Fauret AL, Fiessinger JN, Germain DP, Georgesco G, Hulot JS, De Paepe A, Plauchu H, Jeunemaitre X, Laurent S, Boutouyrie P. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010;376:1476–84. [PubMed: 20825986]
12. Palmeri S, Mari F, Meloni I, Malandrini A, Ariani F, Villanova M, Pompilio A, Schwarze U, Byers PH, Renieri A. Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism. Clin Genet. 2003;63:510–5. [PubMed: 12786757]
13. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673–80. [PubMed: 10706896]
14. Schwarze U, Schievink WI, Petty E, Jaff MR, Babovic-Vuksanovic D, Cherry KJ, Pepin M, Byers PH. Haploinsufficiency for one col3a1 allele of type iii procollagen results in a phenotype similar to the vascular form of ehlers-danlos syndrome, ehlers-danlos syndrome type iv. Am J Hum Genet. 2001;69:989–1001. [PMC free article: PMC1274375] [PubMed: 11577371]
15. Tsipouras P, Byers PH, Schwartz RC, Chu ML, Weil D, Pepe G, Cassidy SB, Ramirez F. Ehlers-Danlos syndrome type IV: cosegregation of the phenotype to a COL3A1 allele of type III procollagen. Hum Genet. 1986;74:41–6. [PubMed: 2875936]
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Author Notes

Web: www.pathology.washington.edu/clinical/collagen

Revision History

• 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