Pathogenesis, Genetics, and Molecular Developments in Vascular Lesion Therapy and Diagnosis

Within the past decade, the genetic etiology of HNLM and other rare overgrowth conditions have been explored and have led to a better understanding of the formation of these lesions, why treatment has not always been effective, and possible new treatment options. Genetic mutations can be divided into somatic or germline mutations. Germline mutations are alterations in the genetic sequence of the gamete, involve all cells in the organism, and can be passed on to future generations. Somatic mutations are post-zygotic DNA variations occurring after fertilization that are more difficult to detect without the use of advanced DNA sequencing technologies. The most commonly identified mutations found in vascular anomalies involve the tyrosine kinase receptor signaling pathway. Through this signaling, the RAS or phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway can be activated. The most commonly associated mutation in HNLM is a postzygotic somatic mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene. Three locations or “hotspots” within PIK3CA are frequently involved in sporadic human cancers and are thought to enhance tissue overgrowth. Samples of affected tissue from patients with isolated HNLM, CLOVES, KTS, or fibro adipose hyperplasia are required to detect PIK3CA hotspot mutations. The majority of the tissue samples revealed activating hotspot mutations in PIK3CA. Interestingly, these exact same mutations are some of the most commonly identified mutations in a large number of human cancers. It is unknown why PIK3CA mutations that occur during early embryonic development can lead to mosaic, vascular overgrowth phenotypes, and yet the exact same mutations occurring in adult tissues can promote tumorigenesis. Clearly, there is much to discover regarding the molecular pathophysiology of these entities. Future work is necessary to understand the molecular pathophysiology of PIK3CA and how it contributes to a variety of rare conditions that occur throughout the body, not just the head and neck.