Targeted management of vascular anomalies

Advances in genetic sequencing technology have enabled identification of the somatic and germline variants that underlie many vascular anomalies. These pathogenic variants often affect one of two signalling pathways: (1) the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway and (2) the RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway. This narrative review aims to synthesize the existing knowledge on the genetic origin of vascular anomalies and the targeted therapeutic approaches. A literature search was conducted using PubMed, Google Scholar and EMBASE, with a key focus on genetic pathways and emerging therapies. mTOR inhibitors have shown efficacy in a range of venous, lymphatic, capillary and syndromic vascular malformations. PIK3CA inhibitors are already commonly used in the treatment of PIK3CA-related overgrowth spectrum (PROS), with current research into new mutant-specific inhibitors aiming to improve selectivity and reduce toxicity. AKT inhibitors are being trialled in Proteus syndrome and PROS. MEK inhibitors have shown efficacy in the treatment of capillary malformations with arteriovenous malformations (CM-AVM) and both MEK and BRAF inhibitors are being investigated for use in extracranial AVMs. Vascular anomalies were previously orphan diseases with minimal effective therapeutic approaches. The discovery of the precise molecular pathways underlying these anomalies has allowed existing drugs to be repurposed for genotype-guided management, enabling a 'personalized' approach to patient care.