Vascular Ehlers–Danlos syndrome

doi:10.1016/j.anngen.2003.07.002

Annales de Génétique

Volume 47, Issue 1, January–March 2004, Pages 1-9

https://doi.org/10.1016/j.anngen.2003.07.002 Get rights and content

Abstract

Vascular Ehlers–Danlos syndrome, also known as Ehlers–Danlos syndrome type IV, is a life-threatening inherited disorder of connective tissue, resulting from mutations in the COL3A1 gene coding for type III procollagen. Vascular EDS causes severe fragility of connective tissues with arterial and gastrointestinal rupture, and complications of surgical and radiological interventions. As for many rare orphan diseases, delay in diagnosis is common, even when the clinical features are typical, leading to inadequate or inappropriate treatment and management. In childhood many individuals with vascular EDS are first thought to have coagulation disorders. In adulthood, four main clinical findings, including a striking facial appearance, easy bruising, translucent skin with visible veins and rupture of vessels, gravid uterus or intestines, contribute to the diagnosis, which can be confirmed by SDS-PAGE studies of type III procollagen molecules synthesis by cultured fibroblasts or by the identification of a mutation in the COL3A1 gene coding for type III procollagen. Vascular EDS is inherited as an autosomal dominant trait. Varied molecular mechanisms have been observed and, of the mutations described to date, most have been unique to each family or “private”, with no correlation between genotype and phenotype. Vascular EDS is of particular importance to surgeons, radiologists, obstetricians and geneticists since, although there is currently no specific treatment for the condition, knowledge of the diagnosis may help in the management of visceral complications, pregnancy and genetic counseling.

Introduction

Ehlers–Danlos syndrome (EDS) is a heterogeneous group of heritable disorders of connective tissue, characterized by skin hyperextensibility, joint hypermobility and tissue fragility [39], [43]. A revised classification has been proposed following elucidation of the biochemical and molecular basis for several subtypes [4]. Vascular EDS (OMIM 130050, also known as EDS type IV or Sack-Barabas syndrome), is of particular importance as this is the only form associated with a high risk of early death due to arterial, intestinal and uterine ruptures [31].

Section snippets

Facial dysmorphism

The distinctive facial features include a pinched nose, prominent staring eyes with periorbital pigmentation and fine telangiectasae of the eyelids [13], high cheek bones and sunken cheeks, thin lips and lobeless ears. However, facial dysmorphism is absent in some cases of vascular EDS and this can be misleading.

Dermatological manifestations

The earliest clinical manifestations of vascular EDS tend to be cutaneous. Patients bruise easily (Fig. 1) despite normal coagulation studies and, in infants, this can lead to

Laboratory diagnosis

Type III collagen is a fibril forming collagen expressed in early embryos and throughout embryogenesis. In the adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and in the skin. Type III collagen is a homotrimer formed by the association of three α1(III) chains. The core of the molecule is a triple helix with an amino acid sequence characterized by Gly-X-Y repeats. To ensure proper assembly of the α monomers, the Gly-X-Y repeats must

Genetic counseling

EDS type IV is a monogenic orphan disease transmitted as an autosomal dominant trait (OMIM 130050). Affected individuals have a 50% chance of passing on the mutated gene to each child. The incidence of de novo mutations is high and sporadic cases account for half of reported cases. Somatic and germ-line mosaicism has been reported [26], [34]. Until the 11th edition of the catalogue of monogenic inherited diseases [24], recessive autosomal transmission of vascular EDS was also considered a

Conclusion

Vascular EDS is a distinct form of EDS. Diagnosis is based initially on clinical findings and is easiest for patients presenting with acrogeria or a first complication. Biological or molecular assays of collagen III can be very helpful in confirming the diagnosis. There are currently no specific treatments, and medical intervention is limited to symptomatic treatment, precautionary measures and genetic counseling. After diagnosis, a specialist in medical genetics should be consulted and

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Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inheritable connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and cutaneous fragility with delayed wound healing. Over and above these common features, they differ in the presence or absence of various organ and tissue abnormalities, and differences in genetic causal mechanisms and degree of severity. They are complex and multisystem diseases, with the majority being highly disabling because of major joint problems and neurosensory deficiencies, and in some cases, they may be life-threatening due to associated complications, especially vascular disorders. In 1997, the Villefranche classification defined 6 subtypes of EDS. However, many other new variants have been described over the last years. The “historical” EDS were characterized by abnormalities in fibrillar collagen protein synthesis. More recently, disorders of synthesis and organization of the extracellular matrix have been shown to be responsible for other types of EDS. Thus, many EDS are in fact metabolic diseases related to enzymatic defects. While there is no curative treatment for any type of EDS, early diagnosis is of utmost importance in order to optimize the symptomatic management of patients and to prevent avoidable complications. Patients must be treated and monitored by multidisciplinary teams in highly specialized reference centers. In this article, we present the current state of knowledge on these diseases that continue to be elucidated thanks to new molecular genetic techniques.
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ReviewVascular Ehlers–Danlos syndrome

Abstract

Introduction

Section snippets

Facial dysmorphism

Dermatological manifestations

Laboratory diagnosis

Genetic counseling

Conclusion

Cardiovasc. Surg.

J. Invest. Dermatol.

Int. J. Cardiol.

Ann. Vasc. Surg.

Ann. Thorac. Surg.

Pediatr. Neurol.

Ann. Emerg. Med.

Am. J. Hum. Genet.

Am. J. Surg.

J. Biol. Chem.

J. Emerg. Med.

Chest

Structure of cDNA clones coding for the entire preproa1(III) chain of human type III collagen

Biochem. J.

Myocardial infarction and coronary artery dissection during pregnancy associated with type IV Ehlers–Danlos syndrome

Am. J. Perinatol.

Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997

Am. J. Med. Genet.

Surgical pitfalls in a patient with type IV Ehlers–Danlos syndrome and spontaneous colonic rupture. Report of a case

Dis. Colon Rectum

Multiple vascular and bowel ruptures in an adolescent male with sporadic Ehlers–Danlos syndrome type IV

Pediatr. Dev. Pathol.

The Ehlers–Danlos syndrome: a heritable collagen disorder as cause of bleeding

Thromb. Haemost.

Human α1(III) and α 2(V) procollagen genes are located on the long arm of chromosome 2

Proc. Natl. Acad. Sci. USA

Spontaneous rupture of liver in a patient with Ehlers Danlos disease type IV

Dig. Dis. Sci.

Ehlers–Danlos syndromes. Clinical, genetic and molecular aspects

Ann. Dermatol. Venereol.

Large kindred with Ehlers–Danlos syndrome type IV due to a point mutation (G571S) in the COL3A1 gene of type III procollagen: low risk of pregnancy complications and unexpected longevity in some affected relatives

Am. J. Med. Genet.

Review
Vascular Ehlers–Danlos syndrome