Elsevier

Matrix Biology

Volume 20, Issues 5–6, September 2001, Pages 327-335
Matrix Biology

Mini review
Molecular genetics of vascular malformations

https://doi.org/10.1016/S0945-053X(01)00150-0Get rights and content

Abstract

Vascular malformations are localized errors of angiogenic development. Most are cutaneous and are called vascular ‘birthmarks’. These anomalies are usually obvious in the newborn, grow commensurately with the child, and gradually expand in adulthood (Mulliken and Glowacki, 1982). Vascular malformations also occur in visceral organs, such as the respiratory and gastrointestinal tract, but are more common in the brain (Mulliken and Young, 1988). These anomalies are composed of tortuous vascular channels of varying size and shape, lined by a continuous endothelium and surrounded by abnormal complement of mural cells. Vascular malformation can be life threatening due to obstruction, bleeding or congestive heart failure. Most anomalies occur sporadically, but there are families exhibiting autosomal dominant inheritance. Genetic studies of such families have resulted in the identification of mutated genes, directly giving proof of their important role in the regulation of angiogenesis.

Introduction

Cutaneous vascular lesions all look very similar at first glance, but there are important clinical and histologic differences. The pattern of growth is a critical determinant in differential diagnosis. Vascular malformations enlarge very slowly, commensurately with the growth of the child. In contrast, the most common vascular tumors, hemangiomas, grow rapidly during the first year of life and spontaneously regress over the ensuing 1–8 years (Mulliken and Glowacki, 1982, Mulliken and Young, 1988). Histologically, hemangiomas are composed of tightly packed sinusoidal channels, lined by plump rapidly dividing endothelial cells. In contrast, vascular malformations are composed of abnormal channels, and the lining endothelium is quiescent. On the basis of their clinical appearance, natural history, and histopathology, vascular malformations are divided into arterio-venous, capillary, lymphatic, venous and combined lesions (Mulliken and Glowacki, 1982). Vascular malformations are developmental defects, probably caused by dysregulation in signaling that regulates proper formation of the vascular tree. Hemangiomas are tumors that express a localized increase in angiogenic growth factors. These differences are supported by the identification of mutated genes that cause specific inherited forms of venous, arteriovenous and capillary-venous malformations, as well as lymphedema.

Section snippets

Venous malformation

Venous malformations (VM) are the most common vascular anomalies seen in referral centers (Fig. 1). Most VMs are cutaneous and intramuscular, but they can occur in any organ. The incidence is not known, but we assess the range to be between 1/5000 and 1/10 000 births. The lesions range in size from very small to extensive. VMs can be flat or raised. They are violaceous to bluish in color, due to stagnation of venous blood within the lesion (Enjolras et al., 1990). Multifocal lesions occur, and

Glomuvenous malformation (venous malformation with ‘glomus cells’)

Glomuvenous malformations (GVM), or venous malformations with ‘glomus cells’, are a subtype of venous anomalies (Fig. 1). Usually, these lesions can be clinically differentiated from the more common VMs (Boon et al., in preparation). GVM lesions are raised, bluish-purple, with a cobblestone surface. They are very painful on palpation. They are rarely encountered in mucous membranes, in contrast to other VMs which commonly occur in buccal and intestinal mucosa, and in other organs (Boon et al.,

Arteriovenous malformation

The most dangerous vascular anomalies are high-flow arteriovenous malformations (AVM) (Fig. 1) and arteriovenous fistulae (AVF). They occur sporadically and manifest, as red, warm, pulsatile cutaneous lesions (Mulliken and Young, 1988). AVMs are perhaps most common in the central nervous system, where they present insidiously or suddenly with neurologic consequences. Histologically, AVM is composed of dysplastic arteries intermingled among arterialized veins with thickened intimal lining.

Cutaneous and cerebral capillary-venous malformation

Although most vascular anomalies are cutaneous, capillary-venous malformations have a predilection for brain. In the past, these lesions were called either ‘cavernoma’ or ‘cavernous angioma’; now the more precise term ‘cerebral cavernous malformation’ (CCM) is preferred. These localized intracerebral lesions cause seizures, hemorrhage, and headaches (Giombini and Morello, 1978). Histologic sections vary between different areas of a lesion as well as between lesions in the same patient.

Lymphedema

Lymphedema is the term used to describe diffuse, subcutaneous swelling, usually involving the lower extremities (Fig. 1). Generalized lymphedema is uncommon. The condition can be congenital (Milroy disease); however, 80% of cases are late-onset (Meige disease) (Mangion et al., 1999) (Table 1). By lymphangiography, lymphedema is characterized by aplasia, hypoplasia, or hyperplasia of lymphatic channels. Lymphedema has strong familial aggregation, up to 35% of patients have a positive family

Conclusions

Vascular malformations of the skin and other organs are intriguing examples of developmental dysmorphogenesis. Their diversity reflects the multiple factors involved in the proper regulation of vasculogenesis and angiogenesis. Molecular discoveries have indicted genes expressed in endothelial cells and involved in receptor signaling (Table 1). These mutated genes encode tyrosine kinase receptors and intracellular signaling molecules. There may also be a role for extracellular matrix components

Acknowledgements

We are grateful to our patients and their families for their participation in these studies. The authors also thank Ms Ana Gutierez for her superb technical assistance. This work was supported by the Fonds Spéciaux de Recherche-Université Catholique de Louvain, the Belgian Federal Service for Scientific, Technical and Cultural Affairs, the FNRS (Fond National de la Recherche Scientifique), and European Commission (grant ERB4001GT963858) (all to M.V., Chercheur qualifié du F.N.R.S.).

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