Pathogenesis of Vascular Anomalies

Abstract

Vascular anomalies are localized defects of vascular development. Most of them occur sporadically, i.e. there is no familial history of lesions, yet in a few cases clear inheritance is observed. These inherited forms are often characterized by multifocal lesions that are mainly small in size and increase in number with patient's age. On the basis of these inherited forms, molecular genetic studies have unraveled a number of inherited mutations giving direct insight into the pathophysiological cause and the molecular pathways that are implicated. Genetic defects have been identified for hereditary haemorrhagic telangiectasia (HHT), inherited cutaneomucosal venous malformation (VMCM), glomuvenous malformation (GVM), capillary malformationarteriovenous malformation (CM-AVM), cerebral cavernous malformation (CCM) and some isolated and syndromic forms of primary lymphedema. We focus on these disorders, the implicated mutated genes and the underlying pathogenic mechanisms. We also call attention to the concept of Knudson's double-hit mechanism to explain incomplete penetrance and the large clinical variation in expressivity of inherited vascular anomalies. This variability renders the making of correct diagnosis of the rare inherited forms difficult. Yet, the identification of the pathophysiological causes and pathways involved in them has had an unprecedented impact on our thinking of their etiopathogenesis, and has opened the doors towards a more refined classification of vascular anomalies. It has also made it possible to develop animal models that can be tested for specific molecular therapies, aimed at alleviating the dysfunctions caused by the aberrant genes and proteins.

Three Case Reports of Simple Vascular Malformations: Inappropriate, Perplexing and Interchangeable Use of Nosology by Clinicians and Pathologists

“…Cutaneous and mucosal CM commonly called portwine stain occur in 0.4-1% of new-born and appear as reddish-pink macules without any thrill or bruit over facial dermatomes supplied by the branches of the trigeminal nerve [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. They occur because of distension of post-capillary venules due to defect in the sensory and autonomic vascular innervations of the capillary plexus, commonly resulting from the somatic mutation of GNAQ and RASA-1 gene [1][2][3][4][5][6][7][8][9][10][11].…”

“…They occur because of distension of post-capillary venules due to defect in the sensory and autonomic vascular innervations of the capillary plexus, commonly resulting from the somatic mutation of GNAQ and RASA-1 gene [1][2][3][4][5][6][7][8][9][10][11]. 90% of the portwine stains affect more than one dermatomes, with the combined affliction of maxillary and ophthalmic dermatomes being the most common [1][2][3][4][5][6][7][8][9][10]. With age the lesions darken in colour and thicken to produce a violaceous coloured cobblestone surfaced vascular lesion [1][2][3][4][5][6][7][8][9][10][11].…”

“…VMs occur in 1-1.5% of live-births and do not show predilection for any gender or race [1,2]. Their etiopathogenesis are not properly understood, though advances made in molecular genetics have improved our insight with the discovery of several inherited mutations [4,5]. The International Society for the Study of Vascular Anomalies (ISSVA) updated April 2014 classification differentiates vascular lesions with proliferative endothelium (vascular tumours) ( Table 1) from structural anomalies (vascular malformations) ( Table 2) [6][7][8][9].…”

“…An interactive portable document format of ISSVA classification is available at www.issva.org [accessed 23 April 2016]. VMs are always present at birth, though they may sometimes become clinically visible only later during early childhood [1][2][3][4][5]. They persist throughout life and grow slowly with the person's biological growth [1][2][3][4][5].…”

“…VMs are always present at birth, though they may sometimes become clinically visible only later during early childhood [1][2][3][4][5]. They persist throughout life and grow slowly with the person's biological growth [1][2][3][4][5]. Unfortunately 50% of the VMs are diagnosed and termed incorrectly as hemangioma because of lack of update and knowledge of these lesion among clinicians and since it is often impossible to differentiate clinically and histopathologically a malformation from a neoplasm [6][7][8][9].…”