Historically, vascular malformations were not thought to be the result of genetic abnormalities because most of those presenting clinically are sporadic. However, research in this field has expanded over the last decade, leading to the identification of genetic defects responsible for several inherited forms of vascular malformations and associated syndromes, which has shed light on the pathogenesis of sporadic lesions. This advancement in the field has not only enhanced diagnostic capabilities but also improved our understanding of the potential role of complex genetic mechanisms in vascular malformation development. This article focuses on genetic contributions of vascular malformations in the context of syndromes and the tests that are available.
Historically, vascular malformations were not thought to be the result of genetic abnormalities because most of those presenting clinically are sporadic. However, research in this field has expanded over the last decade, leading to the identification of genetic defects responsible for several inherited forms of vascular malformations and associated syndromes, which has shed light on the pathogenesis of sporadic lesions. This advancement in the field has not only enhanced diagnostic capabilities but has also improved our understanding of the potential role of complex genetic mechanisms in vascular malformation development.
It is important for pediatricians to recognize genetically determined vascular malformations and their associated syndromes because there are several disease-specific risks, including various forms of cancer, coagulopathies, pulmonary embolism, and cardiac overload. Genetic testing may be extremely useful for clinical management, screening, and treatment decision making but should be performed only with proper education of the patients and their families. The clinical characteristics of vascular malformations are discussed in the article by Marilyn Liang elsewhere in this issue; this article focuses on genetic contributions to vascular malformations, vascular malformations in the context of syndromes, and the tests that are available.
Current knowledge
Vascular malformations are localized structural defects of the vasculature, named after the type of vessel affected. Although some forms of vascular malformations are inherited, a majority occurs sporadically. It is postulated that vascular malformations and some associated syndromes are the result of a somatic mutation creating a mosaic clinical phenotype, in which 2 genetically distinct populations of cells exist within the same individual. These malformations are present at birth, tend to grow proportionately with the child, and do not regress spontaneously. The malformations vary greatly in number, size, and location, and can also occur in the context of syndromes. Table 1 summarizes current knowledge regarding genetic contributions to vascular malformations and syndromes with a significant vascular malformation component.
| Malformation | Mode of Inheritance | Locus | Gene | Mutations | Pathways/Functions |
|---|---|---|---|---|---|
| Capillary malformation | Sporadic | — | — | — | — |
| Capillary malformation-arteriovenous malformation | Autosomal dominant | 5q13-22 | RASA1 | Loss of function | Ras-MAPK pathways; cell growth, proliferation, motility, survival |
| Cerebral cavernous malformation | Sporadic | — | — | — | — |
| Autosomal dominant | 7q11-22 | KRIT1 | Loss of function, somatic second hits | Adaptor proteins, integrin β1 pathway, cell adhesion, migration | |
| 7p13 | Malcavernin | ||||
| 3q26.1 | PDCD10 | ||||
| 3q26.3-27.2 | — | ||||
| Venous malformation | Sporadic | 9p21 | TIE2/TEK | Somatic, gain of function | Tyrosine kinase receptor, EC proliferation, migration, survival; smooth muscle cell recruitment; vascular sprouting and maturation |
| Glomuvenous malformation | Autosomal dominant | 1p21-22 | GLMN | Loss of function, somatic second hit | TGFβ, HGF pathways; protein synthesis; smooth muscle cell differentiation |
| Cutaneomucosal venous malformation | Autosomal dominant | 9p21 | TIE2/TEK | Gain of function | Tyrosine kinase receptor; smooth muscle cell recruitment, vascular sprouting, EC proliferation and migration |
| Lymphatic malformation | Sporadic | — | — | — | — |
| Primary lymphedema (Milroy disease) | Sporadic | 5q35.3 | VEGFR3/FLT4 | De novo, loss of function | Tyrosine kinase receptor; angiogenesis, lymphangiogenesis, EC proliferation, migration, survival |
| Autosomal dominant/recessive | Loss of function | ||||
| Lymphedema distichiasis | Sporadic | 16q24.3 | FOXC2 | De novo, loss of function | VEGF, Notch, Insulin, TGFβ pathways; transcription factor, angiogenesis |
| Autosomal dominant | Loss of function | ||||
| Arteriovenous malformation | Sporadic | — | — | — | — |
| Hereditary hemorrhagic telangiectasia | Autosomal dominant | 9q33-34 | ENG | Loss of function | TGFβ, MAPK pathways; EC hypoxia survival, migration, proliferation; vascular organization |
| Multifocal lymphangioendotheliomatosis with thrombocytopenia | Sporadic | — | — | — | — |
| Blue rubber bleb nevus syndrome | Sporadic | — | — | — | — |
| Maffucci syndrome | Sporadic | — | — | — | — |
| Klippel-Trénaunay syndrome | Sporadic | — | — | — | — |
| PTEN hamartoma tumor syndrome | Autosomal dominant | 10q23 | PTEN | Loss of function, loss of heterozygosity | PI3K/Akt pathway; cellular proliferation, migration, survival; angiogenesis |
| Congenital lipomatosis overgrowth, vascular malformation, epidermal nevus, scoliosis syndrome | Sporadic | — | — | — | — |
| Sturge-Weber syndrome | Sporadic | — | — | — | — |
| Parkes-Weber syndrome (solitary capillary malformation) | Sporadic | — | — | — | — |
| Parkes Weber syndrome (multifocal capillary malformation) | Sporadic | 5q13-22 | RASA1 | De novo, loss of function | Ras-MAPK pathways; cell growth, proliferation, motility, survival |
| Inherited a | Loss of function | ||||
| Proteus syndrome | Sporadic | — | — |
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