Vascular Type EDS

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Ehlers-Danlos Syndrome, Vascular Type

Authors: Pepin, MS; H Byers, MD

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 those with EDS type IV 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 while the remainder have new disease-causing mutations.

Offspring of an affected individual have a 50% chance of inheriting the

disease-causing allele. In families in which the underlying biochemical

abnormality of type III collagen or disease-causing mutation in COL3A1 has

been identified, prenatal testing is possible for fetuses at 50% risk.

Diagnosis

The diagnosis of Ehlers-Danlos syndrome, vascular type, also known as EDS

type IV, is made 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 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 at a conference sponsored by the Ehlers-Danlos

Foundation (USA) and the Ehlers-Danlos Support Group UK at Villefranche in

1997.

Major diagnostic criteria for the vascular type of EDS include the

following:

· Thin, translucent skin (especially noticeable on the chest/abdomen)

· Arterial/intestinal/uterine fragility or rupture

· Easy bruising (spontaneous or with minimal trauma)

· Characteristic facial appearance (thin lips and philtrum, small chin, thin

nose, large eyes)

The presence of two or more major criteria is required for the diagnosis of

the vascular type of EDS; bochemical testing is strongly recommended to

confirm the diagnosis.

Minor diagnostic criteria for the vascular type of EDS include the

following:

· 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

· A family history consistent with autosomal dominant inheritance

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.

Testing

Biochemical testing

Currently, biochemical testing for the vascular type of EDS requires

cultured dermal fibroblasts. Proteins synthesized by these cells are

metabolically labeled with radioactively labeled proline and the proteins

are assessed by sodium dodecyl-sulfate polyacrylamide gel electrophoresis.

The amount of type III procollagen synthesized, the quantity secreted into

the medium, and the electrophoretic mobility of the constituent chains is

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. Biochemical testing for the

vascular type of EDS probably identifies more than 95% of individuals with

structural alterations in the proteins synthesized. False positives appear

to be very rare [Pepin, unpublished].

Molecular Genetic Testing

The molecular diagnosis of the vascular type of EDS relies upon DNA testing

to identify specific disease-causing mutations in the COL3A1 gene. Molecular

testing is available for genetic counseling purposes to individuals with the

biochemically confirmed diagnosis of vascular type EDS.

COL3A1 mutations identified in individuals with the vascular type of EDS

include point mutations (substitutions for glycine in the triple helical

region of the collagen molecule), exon-skipping mutations, genomic

deletions, and other infrequent complex alterations. 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. To date, more than

150 COL3A1 disease-causing mutations have been identified with fewer than a

dozen recurrent mutations.

Genetically Related Disorders

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

A COL3A1 glycine substitution mutation has been identified in one family

with familial aortic aneurysm and in another family with aortic aneurysm.

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 isolated and hereditary aneurysm have revealed no

evidence that type III collagen mutations are causative.

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

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, unpublished].

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

Patients have a lifelong history of easy bruising. Keratoconus, periodontal

disease, and venous varicosities have also been reported. Many children with

the vascular type of EDS have few complications and, in families with

negative family history, the disease is often undetected in childhood.

Vascular complications and gastro-intestinal 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 gastro-intestinal 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 sinus fistula, and cervical artery aneurysm is 28 years.

Gastrointestinal complications occur in about 25% of affected individuals.

The vast majority of GI perforations occur in the sigmoid colon. Rupture of

the small bowel and stomach have been reported, though infrequently. Bowel

rupture is seldom lethal (3%) [Pepin, unpublished]. Recurrent bowel rupture

proximal to the first sigmoid tear is common. Complications resulting from

tissue fragility often delay the recovery from surgery.

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. Surgical intervention for bowel

rupture is necessary and usually life-saving. 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 15% risk

for death from peripartum arterial rupture or uterine rupture.

Prevalence

Estimates of the prevalence of the vascular type of EDS vary from 1: 50,000

to 1: 100,000. 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 type III collagen gene mutations with a mild

phenotype do not come to medical attention and therefore go undetected.