Vascular anomalies include benign or malignant tumors or benign malformations of the arteries, veins, capillaries, or lymphatic vasculature. The genetic etiology of the lesion is essential to define the lesion and can help navigate choice of therapy. . In the United States, about 1.2% of the population has a vascular anomaly, which may be underestimating the true prevalence as genetic testing for these conditions continues to evolve.
Key points
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Considerations for genetic testing include type of DNA, sample type, and breadth and depth of coverage.
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Slow-flow lesions are more likely to be caused by genes in the PI3K signaling pathway.
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Fast-flow lesions are more likely to be caused by genes in the RAS-MAPK signaling pathway.
Introduction
Vascular anomalies include benign or malignant vascular tumors or benign malformations of the arteries, veins, capillaries, or lymphatic vasculature. In the United States, about 1.2% of the population has a vascular anomaly. Individuals with vascular anomalies may have chronic pain, recurrent infections, bleeding, clotting disorders, functional limitations, physical deformities, and poor quality of life. While some may resolve spontaneously, other vascular anomalies can severely decrease quality of life in patients if left untreated and may become life-threatening. Vascular anomalies are classified by the International Society for the Study of Vascular Anomalies. In this review, the authors highlight both vascular tumors and vascular malformations of the head and neck. Vascular malformations may be classified by their vessel type. Accordingly, fast-flow vascular malformations refer to arteriovenous malformations where arteries shunt into veins, and slow-flow vascular malformations refer to malformations formed by dilated venous or lymphatic vessels. Capillary malformations are the dilation of capillaries in large patches or telangiectasias, which are smaller malformations. Additionally, the lymphatic vasculature may develop abnormally which can lead to cystic lymphatic malformations, leading to small or large pockets of dilated lymphatics, lymphedema, the accumulation of lymphatic fluid, or complex lymphatic anomalies, which involve lymphatic malformations affecting multiple organ systems.
There are distinct molecular mechanisms that govern vascular development. Tyrosine kinase receptors, the phosphoinositide-3-kinase (PI3K) and the Rat sarcoma (RAS)-mitogen activated protein kinase (MAPK) pathways are essential components that direct growth and differentiation of endothelial cells ( Fig. 1 ). Other signaling molecules define vessel identity, stability, and remodeling. Pathogenic variants (previously known as “mutations”) in these genes result in a variety of vascular malformations. Identifying the genetic cause can direct medical screening and medical therapy, provide information about prognosis and recurrence risk for other family members, and reassure family members about the exact cause of the anomaly.
The main objective of this review is to define the current known genetic causes of vascular anomalies of the head and neck. To accomplish this, the authors also address relevant topics such as inheritance, a limited review of genetic testing methods, and the molecularly targeted therapies currently in use.
Inheritance Patterns
Vascular anomalies may occur due to a pathogenic variant, a change in a gene that causes a disease phenotype, which can be inherited from family members via autosomal dominant inheritance or autosomal recessive inheritance. In other instances, patients may develop a vascular anomaly due to a pathogenic variant that developed after fertilization in some of their cells, known as somatic mosaicism.
Autosomal Dominant Inheritance
In autosomal dominant inheritance, an individual only needs one pathogenic variant on an allele to display the disease phenotype ( Fig. 2 A ). Thus, autosomal dominant variants may be passed on to the next generation if a child receives the allele with the pathogenic variant from an affected parent. In this type of inheritance, all individuals with a pathogenic variant are affected and there are no carriers. There is a 50% risk of recurrence.
Autosomal Recessive Inheritance
Like autosomal dominant inheritance, pathogenic variants may be passed on to next generations and appear in all cells. However, in autosomal recessive inheritance, two pathogenic variants in trans, one from each parent, are required to develop a disease phenotype ( Fig. 2 B). Thus, parents have the chance of having unaffected children, who did not receive any pathogenic variants, carrier children who have one copy of the pathogenic variant, or affected children who have two copies of the pathogenic variant: one inherited from each parent.
Somatic Mosaicism
Unlike autosomal inheritance, in which pathogenic variants are passed down to offspring through affected germline cells, a pathogenic variant may occur in somatic cells of the body during DNA replication after the zygote was formed, rather than in germline cells that lead to inheritance ( Fig. 2 C). When individuals develop a phenotype in only a portion of their cells, rather than all cells, the pathogenic variant is classified as mosaic. Therefore, a genetic test may only detect the pathogenic variant if it is taken from an area of affected cells. This may complicate genetic testing if the affected site cannot be sampled or remains undetected.
Genetic testing
Selecting the appropriate genetic test for a vascular anomaly requires 2 main considerations: the sample type(s) and the breadth and depth of coverage needed ( Fig. 3 , Table 1 ). It is helpful first to establish whether the clinician suspects a germline or a mosaic cause.
| Phenotype | Genotype | Inheritance | Genetic Testing Options |
|---|---|---|---|
| Infantile hemangioma | N/A | ||
| Posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta/cardiac defects, and eye abnormalities (PHACE) association | N/A | ||
| Pyogenic granuloma | NRAS, HRAS, KRAS, BRAF , and MAP2K1 | Somatic mosaicism | Deep vascular gene panel |
| Tufted angioma | ∗Single cases reported with NRAS , GNA14 | Somatic mosaicism | Deep vascular gene panel |
| Kaposiform hemangioendothelioma | ∗Single cases reported with RAD50 , GNA14 | Somatic mosaicism | Deep vascular gene panel |
| Sporadic arteriovenous malformations | KRAS, BRAF, MAP2K1, HRAS | Somatic mosaicism | Deep vascular gene panel |
| Capillary malformation arteriovenous malformation syndrome (CM-AVM) | RASA1 EPHB4 |
Autosomal dominant | Germline vascular panel; consider whether to include HHT genes |
| Hereditary hemorrhagic telangiectasia (HHT) | ENG , ACVRL1, SMAD4, and GDF2 | Autosomal dominant | Germline vascular panel; consider whether to include CM-AVM genes |
| PTEN hamartoma of soft tissue | PTEN | Autosomal dominant or Somatic mosaicism | Deep vascular gene panel including PTEN or PTEN germline testing depending on the phenotype |
| Mucocutaneous venous malformation | TEK | Autosomal dominant | Germline vascular panel; consider whether deep vascular gene panel would be helpful or if it would be helpful to include GLMN |
| Sporadic venous malformation | TEK PIK3CA (less common) |
Somatic mosaicism | Deep vascular gene panel |
| Blue rubber bleb nevus syndrome | TEK | Somatic mosaicism | Deep vascular gene panel |
| Cystic lymphatic malformation | PIK3CA BRAF, PIK3R1, KRAS (less common) |
Somatic mosaicism | Deep vascular gene panel |
| Mixed slow-flow malformation | PIK3CA | Somatic mosaicism | Deep vascular gene panel |
| Glomuvenous malformation | GLMN | Autosomal dominant | Germline vascular panel; consider whether deep vascular gene panel would be helpful or if it would be helpful to include TEK |
| Verrucous venous malformation | MAPK3K3 | Somatic mosaicism | Deep vascular gene panel |
| Familial cerebral cavernous malformation (CCM) | CCM1 (KRIT1) , CCM2 (MGC4607) , or CCM3 (PDCD10) | Autosomal dominant | Germline CCM gene panel; consider whether deep vascular gene panel would be helpful |
| Sporadic cerebral cavernous malformation | CCM1 (KRIT1) , CCM2 (MGC4607) , or CCM3 (PDCD10), MAP3K3 , PIK3CA , and MAP2K7 | Somatic mosaicism | Deep vascular gene panel |
| Sporadic capillary malformations | GNA11, GNAQ, PIK3CA, PIK3R1 , and AKT3 | Somatic mosaicism | Deep vascular gene panel |
| Sturge Weber syndrome | GNAQ, GNA11 | Somatic mosaicism | Deep vascular gene panel |
| Gorham Stout disease | KRAS | Somatic mosaicism | Deep vascular gene panel |
| Generalized lymphatic anomaly | PIK3CA | Somatic mosaicism | Deep vascular gene panel |
| Kaposiform lymphangiomatosis | NRAS, CBL, HRAS, and PIK3CA | Somatic mosaicism | Deep vascular gene panel |
Sample type considerations include the type of DNA and the type of tissue. Currently, commercial genetic testing laboratories perform genetic testing on genomic DNA, or the DNA that is inside the nucleus of cells. Research has successfully shown that cell-free DNA (cfDNA), the DNA that is free-floating in biological fluids, isolated from blood or lymphatic cyst fluid is an adequate sample type for pathogenic variant detection. , Clinical genetic testing from cfDNA recently became available from blood or lymphatic fluid. The other consideration is the type of tissue. In cases of mosaicism, a tissue sample of the vascular anomaly or “affected” tissue sample is needed. Some genetic testing laboratories will pair testing with an “unaffected” tissue sample such as leukocyte DNA isolated from a saliva or blood sample for genetic comparison. The DNA quality is best when extracted from fresh or frozen tissue samples but newer technology has resulted in improved yields with formalin-fixed paraffin-embedded tissue.
Both the breadth (number of genes) and depth (how many times an area of the genome is sequenced) are important in selecting the type of genetic test. Due to technical sequencing capabilities, tests with greater breadth may often have lower depth of coverage. In general, many panels for germline conditions will have sequencing coverage depth of approximately 30 to 50 × and tend to sequence the protein-coding regions of genes or the “exome” and then analyze a subset of genes. Exome sequencing evaluates the protein-coding regions of genes and genome sequencing will sequence the entire genome. Most genetic testing laboratories will include copy number variant detection with exome or genome sequencing.
Typically, gene panels, exomes, and genomes will not detect low-level mosaic variants or low variant allele fractions (the fraction of reads carrying the mosaic variant compared to the reference sequence). In contrast, vascular malformation gene panels will initially capture specific regions of interest before sequencing, leading to sequencing coverage depth from 500 to 2000 × . This allows for variant allele fraction detection down to 1%. Although cancer gene panels may be used, typically cancer panels report variant allele fractions down to only 5% and may not include all genes for vascular malformations. Additionally, cfDNA panels using digital droplet polymerase chain reaction technology will allow for detection of variant allele fractions below 1%.
Vascular tumors
Infantile Hemangioma
Infantile hemangiomas are the most common pediatric vascular tumors, occurring in about 4% of infants. Risk factors for infantile hemangiomas include multiple gestation, prematurity, low birth weight, White race, female sex, and progesterone therapy, and family history. Infantile hemangiomas are not present at birth, but will undergo a proliferative phase of growth (usually from about 3–12 months of age) followed by an involution stage that can last up to almost 10 years. Infantile hemangiomas are GLUT-1 positive by immunostaining, but currently no specific genetic cause has been identified.
P osterior Fossa Anomalies, H emangioma, A rterial Anomalies, C ardiac Anomalies, and E ye Anomalies Association
Posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies (PHACE) association is the association of segmental infantile hemangiomas of the face with additional findings including posterior fossa abnormalities, arterial anomalies, cardiac malformations (including aortic coarctation), and eye anomalies. Sternal raphe may also be considered. Although extensive genetic research has been performed, a conclusive genetic cause has not been identified.
Pyogenic Granuloma
Pyogenic granuloma, also known as lobular capillary hemangioma, is a benign vascular tumor characterized by a smooth or exophytic pink to red to purple papule present on the skin or mucosa. Typically, histology will show lobular proliferations of capillaries ( Fig. 4 ). Somatic pathogenic variants in RAS-MAPK genes including NRAS, HRAS, KRAS, BRAF , and MAP2K1 likely resulting in activation of the RAS-MAPK pathway have been found in pyogenic granulomas, though BRAF c.1799 T > A appears to be the most common driver pathogenic variant.
Tufted Angioma and Kaposiform Hemangioendothelioma
Tufted angioma (TA) is a benign, childhood, vascular tumor that is typically stable or may regress spontaneously. The genetic cause for TA is also not well established. NRAS p.Q61R and GNA14 were found in tissue from a single individual with TA. , Notably, tufted angioma and Kaposiform hemangioendothelioma (KHE) are thought to be related as they have similar methylation profiles. KHE is a rare, benign vascular tumor that typically presents with reddish-purplish skin lesions with poorly-defined borders. The genetic cause of KHE is poorly defined—a RAD50 variant was identified in one KHE sample and GNA14 was identified in one sample. ,
Fast-Flow Vascular Malformations
Fast-Flow vascular malformations are those involving arteries which have fast flow. These are typically caused by pathogenic variants in the RAS-MAPK pathway (see Fig. 1 ).
Arteriovenous Malformations
Loss of the intervening capillary bed between arteries and veins results in an arteriovenous malformation (AVM) leading to direct connection between a fast-flow artery and slow-flow vein. If visible on physical examination, they may be pulsatile masses with or without a blush. AVMs may lead to pain and bleeding. Histologically, there will be features of both thick-walled arteries and thin-walled, ectatic veins ( Fig. 5 ). AVMs may be sporadic and caused by mosaic, pathogenic variants in genes that lead to activation of the RAS-MAPK pathway. , In the brain, the most common cause is KRAS , followed by BRAF . In contrast, AVMs of the body are usually due to MAP2K1 . Other mosaic causes include BRAF and HRAS . , Laser microcapture dissection demonstrated that somatic pathogenic variants are present in the endothelial cells.
AVMs can also be syndromic. AVMs are caused by germline, monoallelic pathogenic variants in RASA1 or EPHB4 in capillary malformation—arteriovenous malformation syndrome (CM-AVM1 or CM-AVM2) and typically are associated with a capillary malformation. Germline RASA1 or rarely mosaic pathogenic variants in KRAS cause Parkes Weber syndrome characterized by AVMs with capillary malformation and overgrowth. , AVMs combined with mucocutaneous telangiectasias and epistaxis are characteristic of hereditary hemorrhagic telangiectasia (HHT), which can have overlap with EPHB4 -related CM-AVM2. HHT is an autosomal dominant disorder caused by monoallelic pathogenic variants in ENG , ACVRL1, SMAD4, and GDF2 . Somatic, second-hit pathogenic variants are found in the vascular malformations in individuals with CM-AVM or HHT. , Finally, AVMs, usually associated with lipomatous growth, are seen in about 50% of individuals with PTEN hamartoma syndrome due to germline, monoallelic pathogenic variants in PTEN . Rarely, AVMs may also be seen in the spine in individuals with congenital lipomatous overgrowth with vascular anomalies and epidermal nevi (CLOVES) due to mosaic, pathogenic variants in PIK3CA .
Slow-flow vascular malformations
Slow-flow vascular malformations involve vessels with slow flow such as venous, lymphatic, and/or capillary vessels either separately or combined ( Fig. 6 ). Slow-flow vascular malformations can be differentiated from fast-flow vascular malformations by the clinical and radiological aspects of the lesion. Slow-flow vascular malformations can present with pain, swelling, psychological distress because of appearance, and functional limitations though typically will not have the pulsatile finding of an AVM. Slow-flow lesions are more commonly caused by components of the PI3K signaling pathway. , ,
Venous Malformation
Venous malformations (VMs) are one of the most common vascular malformations. VMs are congenital malformations but sometimes they are noticed later in life. VM may present as a bluish or purple compressible lesion. When pheloboliths are present, they may present as firm or hard areas in the lesion. VM can lead to pain, swelling, physical deformities, and functional limitations. There can be a solitary or multiple lesions. Histologically, they show dermal lobular proliferation of variably sized and ectatic thin-walled blood vessels ( Fig. 7 ).
