Ehlers Danlos syndrome – type IV – vascular

Synonyms

4

Overview

Vascular Ehlers-Danlos Syndrome (EDS) is an autosomal dominant defect in the type-III collagen synthesis; now thought to affect approximately 1 in 50,000 to 1 in 200,000. Most are only diagnosed after rupturing, so it is believed that many more may well go undiagnosed. The vascular type is considered one of the more serious forms of Ehlers–Danlos syndrome because blood vessels and organs are fragile and prone to tearing (rupture), with possible life-threatening consequences.

Symptoms

Vascular EDS is characterized by thin, translucent skin; easy bruising; and arterial, intestinal, and/or uterine fragility. Some individuals often share distinctive facial features of a thin nose, thin upper lip, small earlobes and prominent eyes.

Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have vascular EDS. 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 vascular EDS has an estimated 5.3% risk for death from peripartum arterial rupture or uterine rupture. One fourth of individuals with vascular EDS, 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 around 50 years.

Causes

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

Prevention

If you have a personal or family history of Ehlers-Danlos syndrome and you're thinking about starting a family, you may benefit from talking to a genetic counsellor — a health care professional trained to assess the risk of inherited disorders.

Prevention of complications:

Effective interventions shall 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. 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.

Diagnosis

The diagnosis of vascular EDS is based on clinical findings and confirmed by identification of a heterozygous pathogenic variant in COL3A1.

Vascular EDS 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 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 vascular EDS


Minor diagnostic criteria

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

 

Genetic testing - the diagnosis of vascular EDS is established with any one of the following:

  • Identification of a heterozygous COL3A1 pathogenic variant on molecular genetic testing.
  • Abnormalities in synthesis and mobility of type III collagen chains on biochemical analysis of type III procollagen from cultured fibroblasts when vascular EDS is suspected but molecular genetic testing does not identify a COL3A1 pathogenic variant or a variant of uncertain significance is identified.
  • 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 may also be considered. The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • More comprehensive genomic testing (when available) including whole-exome sequencing (WES) or whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene panel that contains COL3A1) fails to confirm a diagnosis in an individual with features of vascular EDS. 

Prognosis

EDS is a lifelong condition. A retrospective review of the health history of more than 1200 individuals with vascular EDS delineated the natural history of the disorder. 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 vascular EDS, but the gender difference in mean survival was not found.

Arterial rupture is the most common cause of sudden death in vascular EDS. Spontaneous arterial rupture most often occurs in the second or third decade, but can occur at any time. 

Treatment

There is no cure for vascular EDS. Treatment is palliative. Close monitoring of the cardiovascular system is crucial. 

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. In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of vascular EDS and its associated tissue fragility. There are no guidelines to direct recommendations for elective repair in individuals with aneurysm(s) and vascular EDS. 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.

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

Resources

1. https://en.wikipedia.org/wiki/Ehlers–Danlos_syndrome

2. Melanie G Pepin, MS, CGC, Mitzi L Murray, MD, MA, Peter H Byers, MD: Vascular Ehlers-Danlos Syndrome. GeneReviews® [Internet]. University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1494/