Glossary

AKT1: This is a human gene. Genetic variants in AKT1 are found in proteus syndrome.
Angiosarcoma: A specific type of malignant vascular tumor
Arteriovenous Malformation (AVM): A fast-flow vascular malformation in which multiple direct connections between the arterial and venous system result in low resistance flow, with consequent enlargement of adjacent arteries and veins (sometimes referred to as ‘feeding vessels’). Approximately one- third of AVMs are evident at birth, but they can present at any age. AVMs tend to gradually enlarge over time, but this is highly variable. Some remain stable in size for long periods. Some AVMs enlarge at puberty and during pregnancy. The genomic causes of AVMs are heterogeneous. Some are due to germline genetic variants, as seen in hereditary hemorrhagic telangiectasia (HHT), capillary malformation AVM (CM- AVM)1 or capillary malformation AVM (CM-AVM) syndrome 2 (CM- AVM1, CM-AVM2) or Cowden syndrome due to germline PTEN genetic variants. However, most AVMs are sporadic and are caused by somatic genetic variants which tend to occur in the RAS/MEK/ERK pathway, the best documented genetic variants being gain of function genetic variants in genes MAP2K1 and HRAS, and less often in BRAF. A minority of AVMs occur as part of a syndrome: capillary malformation AVM (CM-AVM) syndrome; hereditary hemorrhagic telangiectasia (HHT); and PTEN hamartoma syndrome. AVMs are also sometimes seen in neurofibromatosis type 1.AVMs which occur in the brain have traditionally been managed by separate specialists from those occurring elsewhere in the body and therefore tended to be regarded as distinct lesions. With growing evidence that these lesions are caused by the same genetic variants as those elsewhere in the body, it has become clear that differences are likely due to anatomic location rather than intrinsic differences. AVMs in the brain most often remain unrecognized until an episode of bleeding. “AVMs” in the lung and liver are particularly associated with HHT and generally correspond to arteriovenous fistulas.
BRAF: This is a human gene. Pathogenic variants in BRAF are often found in Pyogenic Granuloma but occasionally in other vascular anomalies
Capillary Malformation: In previous ISSVA classifications this term has been attached to both a specific diagnosis of an isolated red cutaneous stain, usually caused by a somatic pathogenic variant in the gene GNAQ, and to a general category of congenital cutaneous vascular malformations characterized by small vessels on pathology. In the current classification the specific lesion has been renamed as ‘port wine capillary malformation’; the term ‘capillary malformation’ is now a subcategory of slow-flow malformations, and may sometimes be applied non-specifically in the process of seeking a specific diagnosis.
Capillary-lymphatic-venous-malformation (CLVM): A type of combined vascular malformations. CLVM with hypertrophy is designated as Klippel-Trenaunay syndrome.
Central Conducting Lymphatic Anomaly (CCLA): Central conducting lymphatic anomaly (CCLA) encompasses disorders that are caused by dysfunction of the thoracic duct and/or cisternae chylae with subsequent reflux and leakage of lymphatic fluid, most commonly into the lungs and/or abdomen. Pleural and pericardial effusions, ascites, and generalized edema are common and can result in organ dysfunction, protein loss, and infections.
CLA: Complex lymphatic anomalies, includes lymphatic malformations that present structural complexity, multisystem involvement and functional impairment.
CLOVES Syndrome: CLOVES is now considered to be a part of the PIK3CA-related overgrowth spectrum. It is a rare, sporadic disorder characterized by tissue overgrowth and complex vascular anomalies. The manifestations are variable ranging from mild to severe anomalies. These abnormalities are typically present at birth, however some, such as fatty overgrowth, progress with age.
CM: capillary malformation
CNS: central nervous system
CVM: CM + VM. Capillary-venous malformation. A type of combined vascular malformations.
Fast-Flow Vascular Malformation: One of the main subdivisions included in the Updated version of the classification for vascular malformations. It is differentiated from slow-flow lesions and developmental anomalies of named vessels lesions. Fast-flow vascular malformations can be subdivided into isolated, multifocal and syndromic lesions. The main change was to use flow velocity as a determinant between lesions with arterial components (fast- flow) and lesions with slow-flow components such as venous, lymphatic and capillary.
Fibroadipose Vascular Anomaly (FAVA): A vascular malformation generally caused by somatic mosaic variants of PIK3CA. It is characterized by a mix of malformed venous and lymphatic elements together with fibrofatty infiltration of muscle. Pain and contracture may be observed.
Generalized Lymphatic Anomaly (GLA): A rare multisystem congenital disease, part of the complex lymphatic anomalies (CLA). There is some overlap with Kaposiform lymphangiomatosis (KLA). GLA is characterized by diffuse proliferation of lymphatic channels in osseous and extraosseous tissues. The pathogenesis includes somatic pathogenic variants in RAS/PI3K/mTOR signaling pathway. Patients with GLA have bone and visceral involvement, but in contrast with Gorham Stout Disease, cortical bone is not affected.
Gorham Stout Disease (GSD): A rare multisystem disease, part of the complex lymphatic anomalies (CLA). Aggressive osteolysis with loss of cortical bone in the context of a lymphatic anomaly, also known as "vanishing bone disease".
Kaposiform Hemangioendothelioma (KHE) : A rare vascular tumor that is typically diagnosed in infancy or early childhood, with some cases present at birth It is an aggressive disease with high potential morbidity, mainly due to associated consumption coagulopathy (the Kasabach–Merritt phenomenon (KMP)), a disorder characterized by severe thrombocytopenia, hypofibrinogenemia and high D-dimers. KHE and tufted angioma are now viewed as part of the same spectrum of disease.
Kaposiform Lymphangiomatosis (KLA): A subtype of complex lymphatic anomaly, with some overlap with generalized lymphatic anomaly. It is a rare aggressive disease characterized microscopically by excessive, dilated and abnormally formed lymphatic channels accompanied by scattered clusters of variably canalized, often hemosiderotic, spindled lymphatic endothelial cells. KLA usually presents during childhood, with respiratory symptoms, bleeding, and subcutaneous mass. Potential complications of KLA include thrombocytopenia and hemorrhage. Somatic pathogenic variants in NRAS have been identified in KLA.
Klippel-Trenaunay Syndrome (KTS) : The term KTS has been used to denote a combination of CM+VM +/- LM + limb overgrowth. It is not a genomically uniform diagnosis. Many severe cases are due to somatic pathogenic variants in PIK3CA and are now recognized as part of the PIK3CA-related overgrowth the diagnosis of diffuse capillary malformation with overgrowth (see DCMO). Other cases with overgrowth and vascular birthmarks in association with higher flow vascular anomalies fit best as “Parkes Weber syndrome”, a separate diagnostic entity. Note: The term Klippel-Trenaunay-Weber syndrome is not correct. It has had moderately widespread use in the pediatric literature, after it appeared in some textbooks, but it is a mixture of two distinct syndromes, Klippel-Trenaunay and Parkes Weber and should not be used spectrum (PROS). Other cases which mimic the definition of KTS are due to GNAQ/GNA11 somatic pathogenic variants and most often best fit with [missing copy here].
Lymphatic Malformation: Slow-flow vascular malformation with lymphatic differentiation, classified as macrocystic, microcystic and mixed. Most lymphatic malformations are associated with a somatic pathogenic variant in PIK3CA, more rarely in BRAF.
Macrocystic LM: Macrocystic lymphatic malformation. LM with predominance of large cystic components. The distinction between macrocystic and microcystic LM is primarily of importance for responsiveness to sclerotherapy treatment and choice of therapeutic agent. There is no precise definition separating the two types, and many lesions are mixed.
Microcystic LM: Microcystic lymphatic malformation. LM with predominance of small and multiple cystic components. The distinction between Macrocystic and microcystic LM is primarily of importance for responsiveness to sclerotherapy treatment and choice of therapeutic agent. There is no precise definition separating the two types, and many lesions are mixed.
mTOR: Mammalian target of rapamycin. Intracellular target in the treatment of some vascular malformations, especially those caused by variants in the PI3Kinase pathway.
Overgrowth: Increase in volume of a body part often seen in association with vascular malformations, although it may also occur independently, as in macrodactyly and facial infiltrative lipomatosis. When used as a diagnosis, this term implies an increase in volume in proportion of multiple tissue types which normally make up the part, so histological examination is often normal. In a limb, there will usually be increased limb length in addition to girth, although if several structures, such as muscles which are otherwise morphologically normal are enlarged without change in limb length, the term can be used. The term ‘overgrowth’ should not be used diagnostically to describe an isolated vascular malformation, in which the proliferation of vascular structures is out of proportion to other tissues.
PIK3CA: This is a human gene. Related to many vascular malformations. Pathogenic variants in PIK3CA are found in lymphatic malformations, venous malformations, Klippel-Trenaunay syndrome, megalencephaly-capillary malformation- polymicrogyria, CLOVES syndrome, CLAPO syndrome and fibroadipose vascular anomaly (FAVA). PIK3CA related overgrowth spectrum (PROS) is a term which has been coined to cover the many various lesions caused by somatic variants in PIK3CA.
PIK3CA Related Overgrowth Syndrome (PROS): This term was introduced by Biesecker in 2014 to refer to a range of conditions characterized by overgrowth of tissues associated with somatic pathogenic variants in the gene PIK3CA. ‘PROS’ has sometimes been used as an inclusive term for all proliferative lesions in which a pathogenic variant in the PIK3CA gene is detected (in which case LM would be considered a type of PROS), but the term is more properly used to describe conditions in which ‘overgrowth’ as defined in this glossary (i.e. growth involving more than one tissue type) is a feature. the list overgrowth disorders caused by PIK3CA somatic mutations has expanded to encompass lymphatic malformation, Klippel-Trenaunay syndrome (KTS), CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal), FAVA (fibrodipose vascular anomaly), megalencephaly-capillary malformation (MCAP or M-CM ), facial infiltrating lipomatosis, regional overgrowth (such as macrodactyly), CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) and cutaneous lesions (seborrheic There are also some patients who have overgrowth in tissues in association with a gain of function pathogenic variant in PIK3CA, who do not fit any recognized pattern, in which case ‘PROS’ or ‘PROS (unspecified)’ may be used as a diagnostic label.
PTEN Hamartoma Tumor Syndrome (PHTS): Is a rare syndrome due to inherited variants in the gene PTEN, with a broad phenotypic spectrum, including macrocephaly, autism spectrum disease, slow and high flow vascular anomalies, tissue overgrowth, hamartomas and increased risk of breast, endometrial and thyroid cancer.
RAF1: A gene related to vascular malformations. Germline pathogenic variants in RAF1 are found in Noonan syndrome 5 (rasopathy with lymphedema).
RAS: A family of genes in which genetic variants have been found in multiple vascular malformations. Originally identified as an oncogene (the term is short for ‘rat sarcoma’) three subtypes were subsequently identified (HRAS, KRAS and NRAS) variants in all of which have been found in vascular malformations. RAS proteins are small GTPases which signal through the MEK/ERK pathway, but also into the PI3 Kinase pathway.
Rasopathy: A group of conditions, including some vascular anomalies in which the causative mutated gene is RAS related genes.
Slow-flow Vascular Malformation: One of the main subdivisions of the updated version of the classification for vascular malformations. The main change was to use flow velocity as a determinant between lesions with arterial components (fast-flow) and lesions with slow-flow components such as venous, lymphatic and capillary. It is differentiated from Fast-flow lesions and developmental anomalies of named vessels lesions. Slow-flow vascular malformations can be subdivided into venous, lymphatic, capillary and combined.
TEK (TIE2) : This is a human gene. Pathogenic variants in TEK (TIE2) are found in VM, sporadic multifocal VM (MSVM), and blue-rubber bleb nevus (Bean) syndrome (all due to somatic pathogenic variants), and in familial VM cutaneo-mucosal (VMCM) due to germline pathogenic variants.
Vascular Anomalies: The main category of disease classified according to cellular and clinical behavior in tumors and malformations .
Vascular Malformation: Originally this was a non-specific term to describe any congenital anomaly affecting the vascular system, including conditions such as absence or duplication of great vessels (truncal anomalies). Over time the term has acquired a more specific meaning in vascular anomalies practice. It is now referred to lesions in which there is an overabundance of specific types of vessels. Vascular malformations are subdivided into fast-flow and slow-flow malformations. Caution is needed when using the term outside this context, and to avoid confusion with the term vascular anomaly.
Vascular Tumors: One of the two main categories of vascular anomalies. Vascular anomalies are didactically divided in vascular tumors and vascular malformations. Vascular tumors are classified in benign, locally aggressive, or borderline and malignant.
Venous Malformation : Venous malformations are due to defective assembly of the venous vasculature. Defined subsets are now recognized. Venous malformations are most often due to pathogenic variants in the TEK (Tie2) gene, but also PIK3CA. Lesions due to glomulin pathogenic variants (GVMs) can mimic venous malformation. Nodular VMs can be seen in KRIT1 mutated CCM patients.