Miikka Vikkula, M.D., Ph.D.
Professor of Human Genetics
de Duve Institute and Université catholique de Louvain
GEHU - B1.74.06, Avenue Hippocrate 74,
phone (direct) : 32 (0)2 764 74 96
fax : 32 (0)2 764 74 60
e-mail: Miikka Vikkula
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1. Pathophysiology of vascular anomalies: Vascular anomalies are localized lesions most commonly observed on the skin, although they can affect any organ, such as the liver, intestine and the brain. They are divided into tumors (hemangiomas) and malformations. Hemangiomas appear soon after birth and affect 10% of Caucasian newborns, whereas malformations are present at birth in 0,3% of children. According to vessel type affected, malformations are subdivided into capillary, venous, lymphatic and arterial malformations. These lesions cause important esthetic discomfort, ulceration, pain, dysfunction of the affected body part or organ, and destruction of adjacent normal tissues. Histologically, the lesions consist of tortuous vascular channels with continuous endothelium and a variable number of mural cells.
Depending on the subtype, the current management is based on medications, laser, sclerotherapy, surgery, and symptomatic treatment. Compression and kinesitherapy are sometimes useful. However, since the lesions are commonly present at birth, slowly expand with the growth of the child, and often invade adjacent tissues and structures in a diffuse manner, curative treatment is rarely possible. To enable development of more specific treatments, we focuse our research on the identification of therapeutic targets by uncovering underlying pathophysiological mechanisms. We take advantage of the inherited nature of some of these lesions for the identification of causative genes.
The main goal of our research is to continue to unravel the inherited and somatic pathophysiologic causes of vascular anomalies, which have so far been unraveled for about 20% of them. If you are a patient, you can find information on how to participate in our studies via the Orphanet and GeneTests web-sites. We also aim to functionally analyze the mechanisms by which the identified genetic alterations induce lesion formation, and alter angiogenesis. For this, we use both in vitro and in vivo analyses, including primary cell lines from lesions, transgenic mouse models, and knock-down zebrafish. As our long-term goal is to help develop novel therapies for these anomalies and other angiogenic disorders, these animal models will be invaluable for preclinical screens.
2. Pathophysiology of cleft lip and palate: Orofacial clefts are the most common craniofacial birth defects with an average of 1/700 live births. Patients often present complications with feeding, speech, hearing, dental functioning and psychological development due to cosmetic problems. Clefts are divided into those affecting the lip with or without the palate (CL/P) and those affecting the palate only (CPO). Moreover, all cleft types can be divided into nonsyndromic and syndromic. They are characterized by a complex etiology with a genetic predisposition combined with an environmental impact. There is a constellation of molecules engaged in complex interactions playing a role in facial development, such as extracellular matrix molecules, transcription factors, and growth factors, such as bone morphogenetic proteins, fibroblast growth factors and members of the transforming growth factor superfamily.
For several years, we have been working with the Cleft Lip and Palate Center of Cliniques universitaires Saint-Luc. We are trying to characterize genetic factors involved both in the inherited as well as the sporadic forms of cleft lip and palate. Information on our projectscan also be found via Orphanet and GeneTests web-sites.
We started our project on van der Woude syndrome (VWS), which is the most common cleft syndrome, and popliteal pterygium syndrome (PPS), an allelic syndrome. The IRF6 gene is now known to be responsible for these two syndromes. In our European cohort, mutations were present in 21/31 of VWS and 10/10 PPS families.
We pooled our enlarged data with those of two large geographically defined cohorts, one from Brazil and one of mixed origin. In both cohorts, we identified mutations in IRF6 in 69% of VWS and 97% of PPS patients, independent of ethnic origin. The distribution of IRF6 mutations was non-random with 80% found in exons 3, 4, 7 and 9 for VWS and 72% in exon 4 for PPS. The high mutation concentration suggests these exons to be of critical importance for IRF6 function in orofacial development. Our findings are of interest for genetic counseling, since some VWS families had only minor anomalies and could thus be confounded with isolated CL/P. Identification of an IRF6 mutation allowed us to precise the increased risk for progeny for such patients from 1/700 (incidence in the general population) to 50% (incidence in VWS cases). Moreover, for future diagnostic IRF6 screen, we propose exons 3, 4, 7 and 9 for VWS and exon 4 for PPS to be first screened because of their high mutation prevalence. This would lower the cost and time of screening.