DISEASE CARD

Disease group Connective tissue disorders
DISEASE NAME EHLERS-DANLOS SYNDROME, VASCULAR TYPE
Synonymous Ehlers-Danlos syndrome IV, Ehlers-Danlos syndrome, arterial type, Ehlers-Danlos syndrome, ecchymotic type, Ehlers-Danlos syndrome, Sack-Barabas type
Estimated prevalence 1 - 9 / 100.000
OMIM 130050
Inheritance Autosomal dominant
Gene (s) COL3A1 (120180)

Definition

The term Ehlers-Danlos syndrome (EDS) does not describe a specific disease but a group of connective tissue disorders that share the clinically manifestations of skin hyperextensibility, articular hypermobility and tissue fragility [1]. In the “Villefranche” classification, the formerly used Roman numerals were replaced by six descriptive main types (Table 1). Besides the six main types, EDS also includes a series of “other” types, that are either not clearly classified or poorly characterized [2, 3].

EDS vascular type (vEDS) is characterized by arterial and gastro-intestinal rupture, rupture of the gravid uterus and extensive bruising. It is caused by mutations in the COL3A1 gene encoding type III collagen (2q32.2) [4]. Transmission is autosomal dominant. One vEDS patient has been reported with autosomal recessive mode of inheritance [5].

Table 1: Villefranche classification of the six main types of EDS.

Descriptive type Numerical type Genes
Classic type EDS I (Gravis)
EDS II (Mitis)
COL5A1
COL5A2
COL1A1
Hypermobility type EDS III TNXB
COL3A1*
Vascular type EDS IV COL3A1
Kyphoscoliosis type EDS VI PLOD1
Arthrochalasia type EDS VIIA
EDS VIIB
COL1A1
COL1A2
Dermatosparaxis type EDS VIIC ADAMTS2

*Only one patient has been reported to carry a mutation in the COL3A1 gene.

Clinical Description

Of all EDS subtypes, vEDS has the worst prognosis because of the risk of potentially fatal vascular and intestinal complications. Excessive bruising is the most common sign and is often the presenting complaint to the pediatrician. This can be so striking that child abuse is suspected. Bleeding from the gums following brushing of the teeth, or profuse bleeding after tooth extraction are also frequent signs. The bleeding tendency may lead to an extensive hematologic evaluation, with the usual result that no abnormality is identified. Other early manifestations include obstetric problems, such as premature rupture of the membranes, congenital club foot or congenital hip dislocation [6].

Unlike in other types of EDS, the skin is nonhyperelastic, thin and translucent, through which the venous pattern over the chest, abdomen and extremities is readily visible. Excessive wrinkling and thinness of the skin over hands and feet may produce an old-looking appearance, also called acrogeria. Unusual cutaneous manifestations include elastosis perforans serpiginosa, keloid formation and Raynaud phenomenon. Patients with a vascular type of EDS often have a characteristic facial appearance, including prominent eyes (due to lack of subcutaneous adipose tissue around the eyes), a thin, pinched nose and small lips, hollow cheeks and lobeless ears.

Hypermobility is usually limited to the small joints of the hands.

The vascular fragility largely dominates the clinical picture. Apart from excessive bruising and bleeding, it leads to precocious and severe varicosities and arterial rupture which can present as acute abdomen, cerebral stroke, hematemesis, renal colic and hematuria, retroperitoneal bleeding, muscle swelling, shock and sudden death, as early as in the third or fourth decade of life. The most common locations of arterial bleeding are in the abdominal cavity and involve medium-sized arteries, such as the renal or splenic arteries, rather than the aorta itself. Besides the vascular ruptures, dangerous internal complications may occur.

Gastro-intestinal perforation is common, and the majority occurs in the sigmoid colon. 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.

Obstetrical complications are not so rare and include vascular, intestinal or uterine rupture, vaginal lacerations, prolapse of uterus and bladder, and premature delivery because of cervical insufficiency or fragility of the membranes. Patients with a vascular EDS who are pregnant should be followed in a high-risk obstetrical program.

Pathogenesis

The condition is caused by mutations in the COL3A1 gene, coding for the a1 chain of type III collagen. This homotrimer is a major structural component of skin, blood vessels, and hollow organs. To date more than 250 COL3A1 mutations have been identified. These include point mutations leading to substitutions for glycine in the triple helical region of the collagen molecule, splice site mutations resulting in exon skips, intron inclusion or complex and multiple outcomes, partial gene deletions, and, less commonly mutations resulting in haplo-insufficiency. Vascular EDS is an autosomal dominant disorder, but parental somatic mosaicism for COL3A1 mutations has been documented.

One case of autosomal recessive inheritance of vEDS has been reported. In a young consanguineous girl of healthy parents a homozygous nucleotide duplication was found, that resulted in a premature termination codon and consequently in nonsense-mediated mRNA decay [5].

Diagnosis

The diagnosis is established by family history and clinical findings. It is confirmed by biochemical protein-based testing of radioactively labeled collagen type III from skin fibroblast cultures. This is a highly sensitive investigation and probably identifies more than 95% of individuals with structural alterations in the proteins synthesized. It allows to detect quantitative (reduced amounts of collagen type III) or qualitative (mutant collagen type III with altered electrophoretic mobility) abnormalities of type III collagen.

Molecular sequence analysis to identify mutations in the COL3A1 gene is available to patients with a biochemically confirmed diagnosis of vascular EDS. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Treatment

Because of the inherent tissue fragility, individuals with vascular EDS should avoid contact sports or isometric exercises (weightlifting), drugs that interfere with platelet function, and anti-coagulation therapy. Aggressive control of the blood pressure in order to reduce the risk of arterial rupture is mandatory. Invasive vascular procedures such as arteriography and catheterization should also be avoided because of the possibility of severe morbidity and frequent mortality, and should be replaced by ultrasonography and/or non-invasive imaging. Because of the great risk of surgical complications, surgical interventions are generally discouraged, and conservative therapy is recommended. If surgery is unavoidable, manipulation of vascular and other tissues should be done with extreme care. 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. In case of bowel rupture, prompt surgical intervention is necessary and usually life-saving. Bowel continuity can be restored successfully in most instances either at the time of initial surgery or in a subsequent repair of a colostomy.

Currently no consensus guidelines exist regarding initial evaluation and follow-up of patients with vascular EDS. Noninvasive evaluation of the arterial tree could help to pinpoint locations of future arterial tears, but no data to assess this idea currently exist. Pregnant women with the vascular type of EDS should be followed in a high-risk obstetrical program. It is not known if the potential benefits of elective caesarian section (decreasing the risk of mortality) outweigh the potential risks (increasing morbidity). Educating the pregnant individual as to possible complications and the need for close monitoring is recommended.

References

1
Beighton P. The Ehlers-Danlos syndromes. In: Beighton P. (ed.) : McKusick's Heritable Disorders of Connective Tissue. 5th ed. St. Louis: Mosby 1993. Pp. 189-251.

2
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. (1998) Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997. Am J Med Genet 77:31-37.

3
Byers PH, Murray ML. (2012) Heritable Collagen Disorders: The Paradigm of the Ehlers-Danlos Syndrome. J Invest Dermatol 132(E1):E6-E11.

4
Germain DP. (2007) Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis 2:32 doi:10.1186/1750-1172-2-32.

5
Plancke A, Holder-Espinasse M, Rigau V, Manouvrier S, Claustres M, Khau Van Kien P. (2009) Homozygosity for a null allele of COL3A1 results in recessive Ehlers-Danlos syndrome. Eur J Hum Genet 17(11):1411-1416.

6
Germain DP, Herrera-Guzman Y. (2004) Vascular Ehlers-Danlos syndrome. Ann Genet 47:1-9.