New clinical and molecular genetic criteria for infantile hemangiomas and venous malformations
(2003)
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- Vascular anomalies belong to a highly specialized field that has evolved at the interface of several medical and surgical specialties. The aim of this thesis is to define our current knowledge of vascular anomalies at the clinical (diagnostic and therapeutic), histological and molecular level. The long-term objective of this dissertation is improved treatment of infantile hemangioma and venous malformation, the two most common problematic lesions referred to centers for vascular anomalies. Hemangioma is the most common tumor of infancy. It is usually harmless with a predictable, benign evolution divided into 3 phases (the proliferative, involuting and involuted phase). We identified a new subtype of infantile hemangioma defined as "congenital hemangioma (CH)" that grows in utero and is fully-grown at birth. Furthermore, we defined two forms of congenital hemangioma: those that regress rapidly after birth (RICH) and those that never involute (NICH) (publication I and II). Around 10% of hemangiomas cause local or life-threatening complications necessitating a pharmacologic therapy, usually systemic corticosteroids. We published a retrospective study that showed there were no long-term complications using corticosteroid (publication III). The identification of these benign tumors in the newborn highlighted the differential diagnosis with known malignant tumors, especially congenital fibrosarcoma. Inspired by two infants referred with misdiagnosis, we evaluated clinical, radiological and hematological criteria that clearly differentiate these entities (publication IV). In addition, we retrospectively reviewed the differential diagnosis and treatment of infantile hepatic vascular anomalies that were either diagnosed as hemangioma or arteriovenous malformation: these high-flow vascular lesions are often confused and are managed differently (publication V). In parallel to the clinical studies, we initiated our first genetic project on venous malformations. Professor Mulliken had collected a family with autosomal dominantly inherited mucocutaneous venous malformations. Using linkage analysis, we first identified the chromosomal locus, VMCM1, on 9p21-22 for the defective gene. Samples collected from additional family members enabled us to narrow the linked region, leading to the identification of mutations in the gene coding for the angiopoeitin receptor TIE2 (publications VI and VII). As we collected more families with venous malformations, we were surprised to find that none of them were linked to the VMCM1 locus. Using immunohistochemical analysis, we confirmed that these families were affected with a specific type of venous malformation called "glomangioma". Linkage analysis led to the identification of an interval on the short arm of chromosome 1, VMGLOM (publication VIII). Positional cloning led to the identification of the mutated gene that we named glomulin [Brouillard, 2002 #1226]. Because of the large number of families who had participated, we were able to study the clinical differences between the 9p21-22-linked venous malformation and the 1p21-linked glomangioma. Based on histological and genetic diagnosis, we established clinical criteria for this differentiation (publication IX). As "glomangiomas" are not tumors but lesions made of dysplastic vessels surrounded by "glomus cells", we renamed these lesions with a more accurate term glomuvenous malformation (GVM). In aggregate, these publications constitute an important step towards more accurate clinical diagnosis and proper management of the two most frequent vascular anomalies referred to specialized centers. The identification of the mutated genes for two distinct types of venous anomaly is an important step towards understanding the molecular mechanisms responsible for these disorders and the possibility of creating animal models.
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Boon, L. M. (2003). New clinical and molecular genetic criteria for infantile hemangiomas and venous malformations. https://hdl.handle.net/2078.5/110820