International Society For The Study Of Vascular Anomalies Research Articles

Massive spinal epidural infantile hemangioma, image findings, and treatment: a case report and review of literature.

Spinal involvement of infantile hemangiomas is rare with the predilection to involve the epidural space. A proper diagnosis might be challenging due to the atypical location and variable/inconsistent use of the International Society for the Study of Vascular Anomalies (ISSVA) classification by radiologists, pathologists, and clinicians. A proper diagnosis of epidural infantile hemangioma is key due to the different aggressiveness of the treatment options with inconstant literature regarding the best available treatment. Herein, we present a case of a massive epidural infantile hemangioma successfully treated with only beta-blocker. We discuss the clinical, MRI, CT, ultrasound, and histological features of this lesion as we review the literature with the objective of addressing some of the confusion surrounding the subject.

Discussion on pathological diagnosis of vascular diseases based on ISSVA classification

The diagnosis of vascular diseases is not only about distinguishing neoplastic or non-neoplastic lesions, but also focusing more on emphasizing the essence of the disease, namely the presence or absence of endothelial cell proliferation, and further to distinguishing true hemangioma tumors or vascular malformation. This article is based on the International Society for the Study of Vascular Anomalies (ISSVA) classification, which is widely used in clinical practice, and discusses the related pathological diagnosis issues of vascular diseases.

Management of Vascular Malformations in the Oral Cavity: Case Report

Vascular anomalies are diverse, and several classifications are available for these anomalies, the most recent and accepted classification is that of the "International Society for the Study of Vascular Anomalies (ISSVA) that was made in 2014 and revised in 2018. It divides vascular anomalies into vascular tumors (including hemangiomas) and vascular malformations. Various treatment modalities are available, including laser therapy, steroid therapy, embolization, blocking therapy, sclerosing therapy, surgery or cryosurgery. This article presents the usefulness of CO2 laser and diode laser for the treatment of vascular anomalies of the oral cavity, while presenting an unusual combination, for the treatment of an oral hemangioma associated with an angiomatous epulis, between sclerotherapy and diode laser. This study not only confirmed the treatment's effectiveness in reducing lesion size and minimizing intraoperative bleeding from the epulis but also highlighted its ability to enhance aesthetic outcomes, patient comfort, and overall satisfaction.

Pediatric Vascular Anomalies: A Clinical and Radiological Perspective.

According to the International Society for the Study of Vascular Anomalies (ISSVA) classification, vascular anomalies include a diverse range of pathologies, classified as either vascular tumors or vascular malformations. This classification, last revised in 2018, aims to explain the biological basis of vascular lesions and help clinicians to manage the anomalies. In vascular tumors, there are proliferative changes of endothelial cells, while vascular malformations primarily consist of structural vascular abnormalities. Infantile hemangioma is the most common soft-tissue vascular tumor. Vascular malformations are an extensive group of malformations of the arterial, venous, and lymphatic systems, either in isolation or in combination. Radiological evaluation plays a key part in the management of pediatric patients with these entities. The understanding of sonography and magnetic resonance imaging findings entails its correlation with clinical findings at the time of scanning.

Incidence of Peripheral Vascular Malformations of Limbs in SMS Hospital Jaipur

Peripheral vascular malformations (PVMs) include a wide spectrum of diseases that can produce potentially life- or limb-threatening complications. The International Society for the Study of Vascular Anomalies (ISSVA) Classification System categorized vascular anomalies into two basic types, the vaso proliferative or vascular neoplasms and developmental vascular abnormalities.
 Method: A retrospective, cross-sectional study was conducted for the period of 2 year. All patients under surgery OPD with a Peripheral limb vascular anomaly excluding upper limbs and lower limbs were taken into the study and investigated and followed up for at least 6 months.
 Result: In this study, out of 38 patients 26 patients (12 (44%) males and 14 (56%) females) were diagnosed withvascular malformation of upper and lower limbs. It is observed that low flow lesions are more common in both upper and lower limbs. Male patients with these lesions tend to present much later in life than female patients.
 Conclusion: AVMs show variance in site and type based on gender. Male patients were more likely present with high-flow AVMs in lower limbs whereas female patients typically presented with low-flow AVMs on the upper extremities.
 Keywords: Peripheral limb vascular malformations, varicose veins, AVM.

Vascular Malformations and Tumors: A Review of Classification and Imaging Features for Cardiothoracic Radiologists.

The International Society for the Study of Vascular Anomalies (ISSVA) classification is a comprehensive histology-based scheme that was updated in 2018. It is important for cardiothoracic imagers to understand this classification to ensure that accurate terminology is used and that archaic terms are avoided when vascular lesions are described. Knowledge of the various malformations (including common conditions, such as venous malformation, arteriovenous fistula, and arteriovenous malformation) and vascular tumors allows for timely diagnosis and appropriate management. This review describes various vascular anomalies, in accordance with ISSVA classification and terminology; highlights key imaging features associated with each; and discusses the role of different imaging modalities. Keywords: Pulmonary, Soft Tissues/Skin, Vascular, Arteriovenous Malformation © RSNA, 2023.

Cutaneous vascular tumors: an updated review

Cutaneous vascular tumors constitute a heterogeneous group of entities that share overlapping morphologic and immunohistochemical features, which can be diagnostically challenging for pathologists and dermatopathologists. Our understanding and knowledge of vascular neoplasms have improved over time, resulting in both a refinement of their classification by the International Society for the Study of Vascular Anomalies (ISSVA) and an improvement in the accurate diagnosis and clinical management of vascular neoplasms. This review article aims to summarize the updated clinical, histopathological, and immunohistochemical characteristics of cutaneous vascular tumors, as well as to highlight their associated genetic mutations. Such entities include infantile hemangioma, congenital hemangioma, tufted angioma, spindle cell hemangioma, epithelioid hemangioma, pyogenic granuloma, Kaposiform hemangioendothelioma, retiform hemangioendothelioma, pseudomyogenic hemangioendothelioma, Kaposi sarcoma, angiosarcoma, and epithelioid hemangioendothelioma.

Clinical phenotype of adolescent and adult patients with extracranial vascular malformation

ObjectiveIn recent years, genotypic characterization of congenital vascular malformations (CVMs) has gained attention; however, the spectrum of clinical phenotype remains difficult to attribute to a genetic cause and is rarely described in the adult population. The aim of this study is to describe a consecutive series of adolescent and adult patients in a tertiary center, where a multimodal phenotypic approach was used for diagnosis. MethodsWe analyzed clinical findings, imaging, and laboratory results at initial presentation, and set a diagnosis according to the International Society for the Study of Vascular Anomalies (ISSVA) classification for all consecutively registered patients older than 14 years of age who were referred to the Center for Vascular Malformations at the University Hospital of Bern between 2008 and 2021. ResultsA total of 457 patients were included for analysis (mean age, 35 years; females, 56%). Simple CVMs were the most common (n = 361; 79%), followed by CVMs associated with other anomalies (n = 70; 15%), and combined CVMs (n = 26; 6%). Venous malformations (n = 238) were the most common CVMs overall (52%), and the most common simple CVMs (66%). Pain was the most frequently reported symptom in all patients (simple, combined, and vascular malformation with other anomalies). Pain intensity was more pronounced in simple venous and arteriovenous malformations. Clinical problems were related to the type of CVM diagnosed, with bleeding and skin ulceration in arteriovenous malformations, localized intravascular coagulopathy in venous malformations, and infectious complications in lymphatic malformations. Limb length difference occurred more often in patients with CVMs associated with other anomalies as compared with simple or combined CVM (22.9 vs 2.3%; P < .001). Soft tissue overgrowth was seen in one-quarter of all patients independent of the ISSVA group. ConclusionsIn our adult and adolescent population with peripheral vascular malformations, simple venous malformations predominated, with pain as the most common clinical symptom. In one-quarter of cases, patients with vascular malformations presented with associated anomalies on tissue growth. The differentiation of clinical presentation with or without accompanying growth abnormalities need to be added to the ISSVA classification. Phenotypic characterization considering vascular and non-vascular features remains the cornerstone of diagnosis in adult as well as pediatric patients.

A Dynamic Web-based Application for the Classification of Vascular Anomalies

The International Society for the Study of Vascular Anomalies (ISSVA) released the most recent version of the classification of vascular anomalies in 2018.1 This revision of the 2014 classification expanded the scope of clinical entities and included molecular diagnostics. The 2018 report incorporated recent discoveries in the field and was released as a 20-page PDF file navigable through embedded links. The links lead users through the classification hierarchy, and each page lists anomalies, their corresponding genetic mutations (if known), and other details. Further information is found in five appendices in the last seven pages of the report. The document is comprehensive, but the structure has drawbacks in usability, organization, and sustainability. The format is rigid and difficult to update. The vascular anomaly field is new and ever growing. In just the past few years, there have been significant advances in discovering new clinical entities and uncovering the genetic basis for these conditions. The PDF-based classification cannot be updated routinely without reformatting entirely. Therefore, this format is unsustainable as new discoveries are made. The PDF format classification also limits organization, ease of use, and navigability. It includes a hierarchy of anomalies and categories organized into tables with internal page links that are difficult to navigate. The embedded links guide users to various pages throughout the document, which provides a nonlinear and somewhat confusing user experience. Additionally, the format of each page was unique (to accommodate custom information), and this lack of standardization stifles the user experience because of the inconsistent location of relevant information. Finally, the indices store information that cannot be placed on the appropriate PDF pages (because of space limitations), which makes navigating back and forth tedious. The aim for a new format was to streamline the design and solve the limitations of the current PDF format. We engineered an interactive web app format, which sustainably supports future updates. The classification is organized into a tree, with nested expandable nodes containing the anomalies in a hierarchical structure, similar to that of a file explorer. With this format, a user can expand the tree to view individual anomalies, associated information, and the entire hierarchy in a common location. The visual hierarchy provides a natural organization of the classification for a more intuitive experience. The app has a consistent format throughout, and it is easily modified. Minor additions and changes can be implemented quickly, without altering or compromising the framework of the format. The web app supports including additional anomaly-specific data through the use of popover buttons, which improves organization while providing comprehensive information. Popovers may contain clinical and radiological images (Figure 1), footnotes for unusual or exceptional cases (Figure 2), genomic information, and others if necessary. Additionally, we included search functionality via autocomplete “smart” select boxes (Figure 3). The user can search for a specific term by selecting it from an alphabetical list, or by typing into a free text field that limits selection to specific options dynamically. When searching for a specific anomaly, the web app opens the tree to the selected entry while briefly highlighting the entry itself and its parent nodes. Separate selectable dialog boxes allow the user to search genes and abbreviations without navigating away (Figure 4).Figure 1.: Expanded tree view of vascular anomalies classification hierarchy. Image popover shows clinical image of infantile hemangioma.Figure 2.: Popover with additional information about rapidly involuting congenital hemangioma.Figure 3.: Search function opens the tree to the selectable term (arteriovenous malformation in this case), automatically scrolls down the page, and highlights hierarchy.Figure 4.: Gene Search and Abbreviation Search dialog boxes with option filtering and autofill. The search buttons remain affixed to the bottom for easy look-up even as one scrolls up and down the tree. One can lookup terms without losing one’s place in the tree.The tree is rendered dynamically from a single data structure, which allows for flexible modification and efficiency. When data are changed it is instantly reflected in the classification. This makes minor or major alterations feasible and practical, in contrast to labor-intense reformats of PDF releases. The vascular anomaly field is changing rapidly with the recognition of new clinical entities and the identification of genes responsible for disease. This app format allows for real-time classification updates. The web app was created using React, a JavaScript library. It is a mobile-friendly application currently hosted at https://vascularanomalies.net. A pure client-side program, it can be embedded easily on the ISSVA website and updated to reflect any future changes rapidly.

An Overview of Vascular Malformations in the Oral and Maxillofacial Region

This review provides a comprehensive overview of vascular malformations in the oral and maxillofacial region, focusing on their historical context, classifications, clinical characteristics, and treatment options. Vascular anomalies (VA) encompass a diverse range of medical conditions affecting the body's vasculature. The study highlights the challenges in diagnosing and managing these conditions due to their varied presentations. It delves into the historical terminology, highlighting how terms like cherry, port-wine stain, and strawberry were used to describe these anomalies. The paper discusses the classification system proposed by the International Society for the Study of Vascular Anomalies (ISSVA), which categorizes vascular anomalies into tumors and malformations based on the presence or absence of endothelial mitotic activity. The importance of accurate histopathological descriptions in diagnosing and treating these anomalies is emphasized. Furthermore, the article provides a detailed discussion of the major types of vascular anomalies, including capillary malformations, venous malformations, arteriovenous malformations, and lymphatic malformations. Each type is characterized by its own unique features, clinical presentations, and associated complications. In terms of treatment, the review discusses various options, including laser therapy, sclerotherapy, embolization, and surgical resection, highlighting the factors that influence treatment decisions, such as lesion type, location, and extent.

Characterization of the Conversion of Meeting Presentation to Publication From the 2016 and 2018 ISSVA Workshops

Objectives: Presentations at scientific conferences and subsequent publications play a critical role in a specialty’s advancement. Previous estimates suggest that about half of the content presented at conferences is not published. The objective of this study is to characterize the conversion from meeting presentations to publications from the 2016 and 2018 International Society for the Study of Vascular Anomalies (ISSVA) Workshops. Methods: The PubMed interface (MEDLINE) and Google Scholar were used to search for published works. Excluded presentations included keynotes, research letters, and education-related theses. Parameters reviewed included conversion rate, time to publication, senior author subspecialty, study design and level of evidence, journal name, and 5-year impact factor. Results: 40.43% of searched conference abstracts were published in peer-reviewed journals. The median publication time from presentation was 16 months (range −28.9 to 41.1). The most frequent specialties of 224 senior authors were: plastic surgery (21.4%), dermatology (20.0%), and radiology (10.7%). Authors published in 111 separate journals, where the majority of publications appeared in Pediatric Dermatology (5.8%). A majority of publications (51.3%) had a case series study design and were level 4 evidence. The median 5-year impact factor was 3.49. Conclusions: From the 2016 and 2018 ISSVA meetings reviewed, less than half of presentations were converted to publications. Studies were published in a wide range of journals, in alignment with specialty. A significant portion of vascular anomalies research at ISSVA that may have the potential to improve patient care does not reach a wider audience.

A clinicopathological reappraisal of orbital vascular malformations and distinctive GJA4 mutation in cavernous venous malformations

Vascular anomalies are common orbital lesions, while variations in previous nomenclature might hamper robust characterization of their clinicopathological and genetic features. We reviewed and reclassified 92 orbital vascular lesions by the modified International Society for the Study of Vascular Anomalies (ISSVA) classification with reappraising clinicopathological parameters of 4 main types of vascular malformations, including orbital venous malformation 1 (OVM1, cavernous venous malformation), OVM2 (varix), OVM3 (infiltrating venous malformation), and arteriovenous malformation (AVM). GJA4, BRAF, and KRAS mutations were assessed by Sanger sequencing. There were 90 cases of vascular malformations, consisting of 60 OVM1 (67%), 13 AVM (14%), 8 OVM2 (9%), 8 OVM3 (9%), and 1 lymphatic-venous malformation (1%). The prevailing OVM1, histologically characterized by well-delineated borders and a uniform cavernous growth pattern, predominantly occurred in intraconal space (57%, P=.019) with an older median age (49 years) and female predilection (73%). OVM2, OVM3, and AVM exhibited differences in the distributions of patients' ages and lesion locations. Sizes of lesions were significantly correlated with periorbital and intraconal/extraconal locations (P<.001). OVM1 had the lowest rate of residual and recurrent diseases (3%). GJA4 mutations were identified in 75% (44/59) of OVM1 but not in OVM2/3 and AVM. No BRAF or KRAS mutations were detected. In conclusion, the modified ISSVA scheme enables meaningful classification of orbital vascular malformations by highlighting the molecular correlation between the distinct clinicopathological features and specific GJA4 mutation in OVM1, which implies OVM1 as a unique variant of venous malformation genetically akin to cutaneous and hepatic counterparts.

Vascular Anomaly Syndromes in the ISSVA Classification System: Imaging Findings and Role of Interventional Radiology in Management.

Vascular anomalies encompass a spectrum of tumors and malformations that can cause significant morbidity and mortality in children and adults. Use of the International Society for the Study of Vascular Anomalies (ISSVA) classification system is strongly recommended for consistency. Vascular anomalies can occur in isolation or in association with clinical syndromes that involve complex multifocal lesions affecting different organ systems. Thus, it is critical to be familiar with the differences and similarities among vascular anomalies to guide selection of the appropriate imaging studies and possible interventions. Syndromes associated with simple vascular malformations include hereditary hemorrhagic telangiectasia, blue rubber bleb nevus syndrome, Gorham-Stout disease, and primary lymphedema. Syndromes categorized as vascular malformations associated with other anomalies include Klippel-Trenaunay-Weber syndrome, Parkes Weber syndrome, Servelle-Martorell syndrome, Maffucci syndrome, macrocephaly-capillary malformation, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis, skeletal, and spinal anomalies) syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome, and CLAPO (capillary malformations of the lower lip, lymphatic malformations of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome. With PHACES (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects and/or coarctation of the aorta, eye abnormalities, and sternal clefting or supraumbilical raphe) syndrome, infantile hemangiomas associated with other lesions occur. Diagnostic and interventional radiologists have important roles in diagnosing these conditions and administering image-guided therapies-embolization and sclerotherapy, and different ablation procedures in particular. The key imaging features of vascular anomaly syndromes based on the 2018 ISSVA classification system and the role of interventional radiology in the management of these syndromes are reviewed. Online supplemental material is available for this article. ©RSNA, 2022.

Venous Malformations.

Venous malformations, the most common type of vascular malformation, are slow-flow lesions resulting from disorganized angiogenesis. The International Society for the Study of Vascular Anomalies (ISSVA) classification offers a categorization scheme for venous malformations based on their genetic landscapes and association with congenital overgrowth syndromes. Venous malformations present as congenital lesions and can have broad physiologic and psychosocial sequelae depending on their size, location, growth trajectory, and tissue involvement. Diagnostic evaluation is centered around clinical examination, imaging evaluation with ultrasound and time-resolved magnetic resonance imaging, and genetic testing for more complex malformations. Interventional radiology has emerged as first-line management of venous malformations through endovascular treatment with embolization, while surgery and targeted molecular therapies offer additional therapeutic options. In this review, an updated overview of the genetics and clinical presentation of venous malformations in conjunction with key aspects of diagnostic imaging and treatment are discussed.

Kaposiform haemangioendothelioma of the spine associated with fixed hyperlordotic deformity and Kasabach-Merritt Syndrome: a case report and literature review.

Kaposiform haemangioendothelioma (KHE) is a rare childhood disease classified by the International Society for the Study of Vascular Anomalies (ISSVA) as a locally aggressive vascular tumor. It has been reported to affect any site, with a predilection for the extremities and trunk. Although it typically manifests as an enlarging cutaneous or soft tissue lesion, less than 10% of cases have no skin involvement, with the retroperitoneum being the most frequently involved extracutaneous site. Approximately twenty cases of KHE with bony involvement have been reported in the literature to date, with only five of those cases involving the spine specifically.We present a, rare case of KHE who presented with progressive fixed hyperlordotic deformity, multiple non-specific spinal lesions, and abnormal blood tests, posing a clinical and radiological diagnostic challenge. Additionally, we conducted a thorough review of the literature to compare and contrast the various multimodality imaging manifestations of KHE involving the spine.

The International Society for the Study of Vascular Anomalies (ISSVA) ontology

The International Society for the Study of Vascular Anomalies (ISSVA) provides a classification for vascular anomalies that enables specialists to unambiguously classify diagnoses. This classification is only available in PDF format and is not machine-readable, nor does it provide unique identifiers that allow for structured registration. In this paper, we describe the process of transforming the ISSVA classification into an ontology. We also describe the structure of this ontology, as well as two applications of the ontology using examples from the domain of rare disease research. We used the expertise of an ontology expert and clinician during the development process. We semi-automatically added mappings to relevant external ontologies using automated ontology matching systems and manual assessment by experts. The ISSVA ontology should contribute to making data for vascular anomaly research more Findable, Accessible, Interoperable, and Reusable (FAIR). The ontology is available at https://bioportal.bioontology.org/ontologies/ISSVA.

The dural angioleiomyoma harbors frequent GJA4 mutation and a distinct DNA methylation profile

The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of “dural angioleiomyomas” (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.

A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies

Vascular anomalies represent a diverse group of disorders classified broadly as malformations or tumors and include the second most common hereditary bleeding disorder worldwide, hereditary hemorrhagic telangiectasia (HHT). Patients with HHT and other vascular anomalies suffer morbid consequences of these diseases, including bleeding, thrombosis, anemia, localized intravascular coagulation, tissue overgrowth, infections, and other complications. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis, and the treatments for vascular anomalies are rapidly evolving. Recent discoveries have elucidated the molecular basis of a number of common and uncommon vascular anomalies. HHT occurs due to mutations in the transforming growth factor beta (TGF‐β) pathway, resulting in vascular endothelial growth factor excess. Complex vascular anomalies including Klippel‐Trénaunay syndrome (KTS) and arteriovenous malformation (AVM) may occur due to mutations in the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. The discovery of the pathophysiologic mechanisms driving these diseases has led to improved phenotype–genotype correlation and the opportunity to target molecular pathways with medical therapies. Therefore, targeted agents have quickly become a standard of care in the treatment of vascular disorders (particularly HHT). Herein, we provide a case‐based approach to the use of antiangiogenic therapies including bevacizumab and pazopanib for the treatment of bleeding in HHT and the use of mammalian target of rapamycin (sirolimus), PIK3CA (alpelisib), and MEK (trametinib) inhibitors in the treatment of complex vascular anomalies.

Interventional Treatment Options in Children with Extracranial Vascular Malformations.

Extracranial vascular malformations vary greatly and belong to the complex field of orphan diseases and can involve all segments of the vascular tree: arteries, capillaries, and veins, and similarly the lymphatic system. The classification according to the International Society for the Study of Vascular Anomalies (ISSVA) represents an important guidance for selecting appropriate therapy. Although many of the principles of endovascular treatment, including image-guided sclerotherapy and embolization, are similar in adult and pediatric practice, there are some distinct differences regarding the treatment of vascular malformations of children. Thus, it is crucial to involve longer-term plan about managing these chronic diseases and their impact on a growing child. This review provides a detailed overview over the clinical presentation of venous, lymphatic, and arteriovenous malformations in children and emphasizes the specifics of their interventional treatment options, including distinct pediatric dose limitations and procedure-related side effects.

How we approach the use of sirolimus and new agents: Medical therapy to treat vascular anomalies.

Vascular anomalies (VAs) are a heterogeneous group of primarily congenital tumors and malformations. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis. Recent discoveries evaluating the genetic causes of VAs have revealed that they are due to mutations in cancer pathways, including the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. These discoveries have led to improved phenotype-genotype correlation and have expanded medical therapy for this group of unique disorders.