A Primer on a Comprehensive Genetic Approach to Vascular Anomalies

Abstract

The field of vascular anomalies has grown tremendously in the last few decades with the identification of key molecular pathways and genetic mutations that drive the formation and progression of vascular anomalies. Understanding these pathways is critical for the classification of vascular anomalies, patient care, and development of novel therapeutics. The goal of this review is to provide a basic understanding of the classification of vascular anomalies and knowledge of their underlying molecular pathways. Here we provide an organizational framework for phenotype/genotype correlation and subsequent development of a diagnostic and treatment roadmap. With the increasing importance of genetics in the diagnosis and treatment of vascular anomalies, we highlight the importance of clinical geneticists as part of a comprehensive multidisciplinary vascular anomalies team.

Keywords: anomalies; genetic; mutation; somatic; vascular malformations.

Figure 1

Germline vs. somatic mutations. Germline mutations are found in one or more of the parental gametes and thus subsequently affect all of the cells of the offspring. Somatic mutations arise in a non-gamete cell of the affected offspring and therefore are present in only 1 area or tissue type and are not in the offspring's gametes. Testing for germline mutations can be done on peripheral blood, but testing for somatic mutations requires biopsy of the affected tissue with subsequent DNA analysis. Peripheral blood and/or unaffected tissue may sometimes be sent along with affected tissue for comparison when searching for somatic mutation.

Figure 2

Genetic pathways implicated in vascular anomalies. The majority of identified mutations in vascular anomalies occur within two key intracellular signaling pathways—the RAS/MAPK and PI3K/AKT/mTOR pathways. The PI3K/AKT/mTOR pathway is crucial for many cellular processes, including cell cycle regulation, proliferation, and migration, and is often termed the “anti-apoptosis pathway.” Several activating mutations within this pathway are associated with vascular anomalies and complex vascular syndromes. The RAS/MAPK pathway is also crucial for cell cycle regulation, proliferation and migration, and is often referred to as the “proliferation pathway.” Several vascular anomalies are associated with mutations in this pathway and frequently termed “rasopathies.” There is also crosstalk between these 2 main pathways. The TGF-β Signaling Pathway is also key for regulation of numerous biological processes, has been implicated in the pathophysiology of hereditary hemorrhagic telangiectasia. Each pathway and their overlap are demonstrated pictorially here. The known associations with vascular malformations and syndromes are highlighted in red.

Figure 3

Patients with vascular anomalies. This panel of patient photographs shows a sampling of some of the physical exam findings in a few key disorders. (A) Shows a patient with the typical capillary malformations seen in patients with RASA1 mutation found on the lower extremity. (B) Shows a patient with Blue Rubber Bleb Nevus syndrome and the typical venous malformations seen here on the tongue. (C) Shows a patient with a large lymphatic malformation of the left upper extremity. The patient is several months into treatment with sirolimus. (D) Shows a young child with an infantile hemangioma of the cheek. (E) Shows the somatic overgrowth, capillary malformation, prominent superficial veins, and lymphangiomas in a patient with CLOVES syndrome. (F) Shows a patient with PTEN hamartoma syndrome and an intramuscular vascular malformation of the forearm/wrist. (G) Shows an infant with a Kaposiform hemangioendothelioma who presented with Kasabach-Merritt syndrome.

Figure 4

Diagnostic algorithm for vascular anomalies. This figure gives a suggested diagnostic algorithm for the initial evaluation and next steps when evaluating a patient with a vascular malformation or tumor. It is not all inclusive, but gives suggestions based on initial characteristics of the lesion and highlights key/critical steps that should not be missed. GLA, generalized lymphatic anomaly; KLA, Kaposiform lymphatic anomaly; CCLA, central conducting lymphatic anomaly; GSD, Gorham Stout Disease; LIC, localized intravascular coagulation; KTS, Klippel Trenaunay Syndrome; PROS, PIK3CA related overgrowth spectrum; BRBN, Blue Rubber Bleb Nevus; IH, infantile hemangioma; CH, congenital hemangioma.