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Year : 2021  |  Volume : 22  |  Issue : 1  |  Page : 1-11

Genetics of Vascular Malformations: Current Perspectives

Paediatric Dermatology Unit, Women and Children Hospital, Kuala Lumpur, Malaysia

Date of Submission17-Jul-2020
Date of Decision27-Aug-2020
Date of Acceptance27-Sep-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Kin Fon Leong
Paediatric Dermatology Unit, Hospital Tunku Azizah, Jalan Pahang, 50586, Kuala Lumpur
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.IJPD_175_20

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For decades, vascular anomalies are categorized as either vascular tumors or malformations based on their onset, clinical course, radiologic, and histologic features. Owing to the heterogeneity of vascular anomalies, they are frequently misdiagnosed. With the advent of massively parallel next-generation sequencing, the molecular landscape of vascular anomalies is rapidly evolving and recent discoveries have shed light on the genetic basis and classification of these vascular disorders. The genotype-phenotype correlation will provide a more precise classification of vascular anomalies and form the basis for future targeted pharmacologic therapy. Thus far, inhibitor of mTOR, AKT1, and PIK3CA (sirolimus, miransertib, and alpelisib) have promising clinical results. In vascular malformations, majority of sporadic cases are due to somatic mutations that disrupt the main endothelial receptor intracellular signaling pathways, i.e., PIK3CA-AKT-mTOR, RAS - MAPK – ERK, and SMAD signaling pathways. Most of the sporadic vascular malformations are caused by somatic mutations that are acquired after fertilization, instead of being inherited from his parents. In general, this type of mosaicism is not inherited, except when the mutation affects the gonads.

Keywords: Genotype-phenotype, next-generation sequencing, somatic mutation, vascular malformations

How to cite this article:
Leong KF. Genetics of Vascular Malformations: Current Perspectives. Indian J Paediatr Dermatol 2021;22:1-11

How to cite this URL:
Leong KF. Genetics of Vascular Malformations: Current Perspectives. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 May 6];22:1-11. Available from: https://www.ijpd.in/text.asp?2021/22/1/1/305804

  Introduction Top

Vascular anomalies represent a broad spectrum of vascular disorders ranging from a simple and self-limiting birthmark, such as nevus simplex, to life-threatening entities, such as kaposiform hemangioendothelioma and angiosarcoma. In the early 1980s, Mulliken and Glowacki proposed a classification that divides vascular anomalies into two major categories: vascular tumors and vascular malformations based on their clinical, radiologic, and histologic features.[1] Vascular tumors are true neoplasms that demonstrate active proliferation by endothelial cell hyperplasia histologically and rapid disproportionate growth clinically, whereas vascular malformations have a quiescent endothelium, and they do not exhibit the markers of proliferation seen in vascular tumor [Table 1]. Clinically, vascular malformations are fully formed at birth and grow proportionately with the somatic growth of the child.[2] Still, much confusion exists in the medical community, mainly due to inaccurate and inconsistent use of nomenclature in the literature, immense phenotypic diversity even within the same category and our ignorance of their pathogenesis. The multidisciplinary International Society for the Study of Vascular Anomalies (ISSVA) was formed in 1992 to create a uniform nomenclature that would facilitate research and clinical practice. Beginning in 1994, the genetic basis of inherited vascular anomalies began to be unraveled using conventional method, such as sanger sequencing. However as the majority of sporadic vascular lesions are due to somatic mutation with low mutant allele frequency, the genetic basis of most vascular anomalies has remained unknown because of the limited sensitivity of conventional methods. Since the early 2010s, the development of high throughput next-generation sequencing has enabled the identification of low-level somatic mutations in sporadic cases of vascular anomalies, and these findings have brought tremendous progress in classification, diagnosis, and treatment options. In this article, we will focus on the genotype-phenotype correlation of vascular malformations.
Table 1: Features of vascular tumor and malformation

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  Genetics of Vascular Malformations Top

Most of us are familiar with germline mutations that can pass on to offspring based on Mendel's laws of inheritance (autosomal, sex-linked, and mitochondrial). However to understand the genetics of vascular malformations, we need to understand a few new genetic terms and concepts.

  Mosaicism, Somatic Mutation, and Timing of Mutation Event Top

Genetic mosaicism should not be uncommon, considering that about 100 trillions cell in a newborn are derived from a single fertilized zygote through cycles of mitosis and DNA replication [Figure 1] and [Figure 2].
Figure 1: Somatic mutation and germline mutation

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Figure 2: Somatic mutation in autosomal dominant disorders

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Mosaicism is a well-described phenomenon in which individuals possess two or more populations of genetically distinct cells as a result of somatic mutation. Somatic mutation is mutation that is acquired after fertilization instead of being inherited from his parents. The mosaic forms of nonlethal autosomal dominant skin disorders have been described as type 1 or 2 segmental mosaicism. In vascular malformations, the clinical severity depends on the timing of the mutational event in the development of the embryo in utero. When the mutations occur during early embryonic mitoses, the clinical phenotype would be widespread across multiple tissues and body segments. If it occurs later, the phenotype will be milder and confined to a single segment. The mosaic mutation may be limited to a specific tissue, different among different tissues, and the levels of mosaicism often are too low to be detected by conventional diagnostic methods. With the rapid advancement of sequencing technologies over the last two decades, it is becoming feasible to detect low level mosaicism (<5%–10%) from somatic tissue samples. Clinically, mosaic skin disorders often come to the attention of pediatric dermatologists because of early-onset patterned or patchy skin lesions that follow the five archetypical patterns of cutaneous mosaicism: blaschko, phylloid, checkerboard, large patches without midline separation, and lateralization.[3],[4],[5],[6]

  Capillary Malformation Top

Capillary malformation (CM) is the most frequent vascular malformation with an incidence of 3 in 1000 live birth.[7] It is a form of slow-flow vascular malformation composed of the increased number of dilated dermal capillaries or venules, forming a flat, pink-red-purple macule or patch. CM is present at birth, grows in size proportionately with the child's body part with no tendency toward self-regression. Over time, it may develop a dark purplish color, affected skin often thickens and becomes nodular with underlying soft-tissues hypertrophy. Soft tissue or bone hypertrophy, the development of vascular nodules, occurs in about two-thirds of patients by the age of 50 years.[8],[9] Confusion originated from an excessive number of descriptive terms that have been applied to it, such as angel kiss, stork bite, salmon patch, port-wine stain, nevus simplex, nevus flammeus, and many more. CMs include a wide variety of vascular stains with different colors, patterns, and associated findings. Thus far, there are at least 20 distinct types of CMs are designated by specific names.[10] The discovery of several somatic and germline mutations in various CMs has partly explained and reinforced their differences, but the precise diagnosis of these different types of CM is still remains challenging. In this article, we propose classifying CMs into eight groups [Table 2] and [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d. They may present as an isolated lesion or associated with various congenital syndromes, such as  Sturge- Weber syndrome More Details More Details (SWS), Klippel-Trenaunay syndrome, Parkes-Weber syndrome (PWS), CLOVE syndrome, and Proteus syndrome. In pathogenesis of CMs, there are at least two major postulations, i.e., nerve denervation and genetic mutations.[11] Recent discoveries of type 1 segmental mosaic mutations in the GNAQ and GNA11 in skin lesions of PWS/SWS/overgrowth with a low-level mutation support the genetic mutation theory.[12],[13],[14] These somatic mutations lead to the dysregulated vascular MAPK and/or PI3K signaling pathways during human embryonic development, thus contribute to the pathogenesis of PWS/SWS/Overgrowth. Other key genes implicated are PIK3CA and AKT in geographical type CM, STAMBP in blotchy type CM, respectively. By contrast, CM-arteriovenous malformations (AVM) is an example of type 2 segmental mosaicism that is caused by loss of function mutations of the RASA 1 or EPHB4.
Figure 3: Types of capillary malformations. (a) Classical capillary malformation. (b) Geographical type capillary malformation. (c) Cutis marmorata telangiectatic congenital (d) Angiokeratoma

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Table 2: Types of capillary malformations

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  Venous Malformations Top

Venous malformations (VMs) are the most frequent vascular malformation referred to vascular anomalies clinics.[15],[16],[17] They can be divided into four groups according to ISSVA classification [Table 3]. The diagnosis of VMs can usually be made clinically as they typically present as soft, compressible, blue-colored lesions on the skin and/or mucosal surfaces [Figure 4]. However, clinic-radiological correlation with non-invasive imaging, i.e., Doppler ultrasound and contrast magnetic resonance imaging may be needed for deeper and complex lesions. Diagnostic skin biopsy is rarely required except for glomuvenous and verrucous VM.[18] All VMs are present at birth, if located deep, they may not be detected clinically until adolescent. They are known to grow proportionately with the child, but rapid growth may occur during puberty, pregnancy, or traumatic injury. Up to 80% of VMs are located in the head, neck, and extremities, 20% in the trunk.
Figure 4: Types of venous malformations. (a) Venous malformations on skin. (b) Glomuvenous malformation. (c) Verrucous venous malformation

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Table 3: Different types of venous malformation

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  Common Venous Malformation-Unifocal Top

Common unifocal VM [Figure 4]a is due to single somatic mutation of the TEK or PIK3Ca gene.[19] Gain-of-function mutations in the TEK gene, which encodes the TIE2 receptor expressed primarily on venous endothelial cells, are found in about half of sporadic VM. In addition, activating mutations in the PIK3CA gene are found in half of the TIE2 mutation-negative VMs. The remaining TIE2/PIK3CA mutation-negative VMS are likely caused by infrequent genes associated with PI3K and MAPK signaling pathway.[20],[21]

  Common Venous Malformation-Multifocal Top

Blue rubber bleb nevus syndrome

It is a rare, sporadic, and severe disorder featured by tens-to-hundreds of cutaneous and internal VMs that often increase in size and number with age. Skin lesions are generally soft, compressible, dark blue papules, and nodules. Gastrointestinal (GI) lesions are pathognomonic and they can occur anywhere on mucous membranes from the mouth to the anus. Bleeding from the fragile GI lesions often lead to iron deficiency anemia, necessitating repeated blood transfusions. Somatic activating mutations in TEK encoding TIE2 were discovered in the individual with blue rubber bleb nevus syndrome (BRBNS) and determined as the cause of this condition.[22]

  Familial Cutaneous and Mucosal Venous Malformation Top

Familial cutaneous and mucosal venous malformation (FCMVM) follows an autosomal dominant pattern of inheritance that characterized by small, multifocal, and hemispherical bluish papules and nodules. Unlike individuals with BRBNS, these patients do not develop intestinal VMs and GI bleeding. It is because of a somatic second-hit TEK mutation among individuals who already carry a germline TEK mutation. Hence, individual with FCMVM has one inherited germline and one somatic TEK gene mutation. (Type 2 segmental mosaicism).[23] The gain of function mutation of TEK results in ligand-independent phosphorylation of TIE2 receptor and constitutive activation of TIE2-mediated signaling through pathways including AKT/PI3K/mTOR and MAPK/ERK. The activation of these pathways directly enhances angiogenesis and reduce endothelial cell apoptosis, therefore leads to abnormal vascular morphogenesis.

  Glomuvenous Malformation Top

Glomuvenous malformation (GVM) presents as a localized or segmental collection of blue to violaceous nodules or coalescing plaques. These vascular lesions are firmer, less compressible than common VM, and sometimes are painful to palpation [Figure 4]b. They can occur at any site on the skin but rarely affect mucous membranes. Histologically, GVM is differentiated by the presence of alpha-actin positive glomus cells around loose distended vein-like channels. Studies have shown that GVM is transmitted as an autosomal dominant trait caused by loss of function mutations in the GLMN gene.[24] However even within the same family with the same germline mutation, there is a wide phenotypic variation and incomplete penetrance, which is 92.7% at 20 years of age. It suggests that an additional genetic event might trigger the formation of GVM lesions and the Knudson's two-hit model could explain the variable expressivity of GVMs with regard to size, number, and localization of lesions. The somatic 2nd hit mutations lead to loss of heterozygosity and localized complete absence of glomulin protein. Glomulin proteins are expressed in endothelial and perivascular smooth muscle cells. Mutation in GLMN gene enhances signaling via the PI3K/mTOR pathway that results in abnormal differentiation of the vascular smooth muscle cells and defective formation of vascular bed because of inappropriate remodeling.

  Verrucous Venous Malformation Top

Before the updated ISSVA 2018 classification, its nature was unclear because it exhibits clinical features similar to those seen in vascular malformations but expresses an immunohistochemical profile similar to vascular tumors (GLUT-1 positivity). In 2015, it finally has been concluded as vascular malformation as genetic analysis has identified somatic mutations in the MAP3K3 gene in 60% verrucous VM tissues.[25],[26] Verrucous venous malformations present initially as nonkeratotic, violaceous macules at birth or during early childhood, whereas the keratotic verrucous component typically develops over time following frequent trauma and secondary infections. The degree of hyperkeratosis is widely variable and may lead to pain, pruritus, smelly discharge, and bleeding. Most lesions are found on lower extremities with unilateral involvement and sometimes show a linear or Blaschkoid-like distribution [Figure 4]c Histologically, it resembles angiokeratoma with epidermal hyperkeratosis, irregular acanthosis, papillomatosis, and aberrant vascular channels in the dermis. However, in contrast to angiokeratoma, the clusters of malformed dermal venule-like channels in verrucous VMs also affect the lower dermis and subcutaneous tissue. Immunostaining showed focal GLUT1 endothelial positivity and low-level MIB-1 reactivity.

  Common Cystic Lymphatic Malformation Top

Common cystic lymphatic malformations (LMs) are congenital lesions of the lymphatic vessels [Table 4] and [Figure 5]a. They are further classified into three groups: macro-cystic, micro-cystic, or mixed. Involvement of superficial and small (<2 cm) lymphatic vessels is termed microcystic LM, while the involvement of deeper lymphatic vessels that larger than 2 cm radiologically is termed macro-cystic LM. Clinically, microcystic LMs are characterized by multiple clusters of translucent or hemorrhagic vesicles resembling frog-spawn. Additional clinical findings are intermittent bruising, lymph leakage, inflammatory flares, and infection over the affected regions. It may manifest at birth or later in life. Common locations are the proximal limbs and chest. As microcystic LMs infiltrate tissues diffusely and might connect to deeper lymphatic vessels, lesions are often much more extensive than clinically expected from the number of vesicles visible on its surface. As a result, excision or sclerotherapy is often followed by recurrences. The archaic term “cystic hygroma” generally referred to the macro-cystic variety that represents subcutaneous collections of interconnected, large lymphatic cysts lined by a thin endothelium. Clinically, they appear as skin colored, soft subcutaneous swelling with positive transillumination test. They often affect the neck, armpits or groin, and lateral chest wall. Spontaneous hemorrhage inside a cyst or secondary infection creates sudden enlargement, which may be life-threatening if the neck is involved. They may be associated with Turner and Noonan syndrome. They are caused by somatic activating mutations in PIK3CA. Mutations in PIK3CA have been found in 16/17 specimens from the Boston children's hospital (Mutant Allele Frequency: 0.8%–10%) that leads to activation of the AKT/mTOR cascade that regulating cell growth, proliferation, and migration.[27],[28],[29]
Figure 5: Lymphatic malformations. (a) Macrocystic and microcystic lymphatic malformations. (b) Milroy disease with bilateral lower limbs lymphedema

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Table 4: Different types of lymphatic malformations and their genotypes

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  Lymphedema Top

Lymphedema consists of an accumulation of interstitial fluid provoking swelling of the affected limb. It is sub- divided into congenital lymphedema, with variable age at onset, and acquired lymphedema, which can be due to, for example surgery or infection. Over 20 genes have been identified to be mutated in different types of primary lymphedema and some of them are listed in [Table 4].[30] The classical form is Milroy disease [Figure 5]b, an autosomal dominant disorder that caused by inherited loss of function mutations in the VEGFR3 gene. It often presents at birth or infancy with swellings of both lower extremities.[30],[31],[32]

  PIK3CA-Related Overgrowth Syndrome Top

PIK3CA related overgrowth syndrome is an umbrella term that covers a wide spectrum of clinical phenotypes, ranging from isolated digit enlargement to segmental overgrowth of the limbs, abdomen, or brain, often in association with vascular malformations. It is caused by activating somatic mutations in the PIK3CA gene, which leads to the uncontrolled activity of the phosphatidylinositol 3-kinase pathway and excessive endothelial proliferation. According to ISSVA 2018, this spectrum includes: [Figure 6]a and [Figure 6]b.
Figure 6: PIK3CA related overgrowth syndrome its spectrum. (a) Klippel trenaunay weber syndrome. (b) CLOVE syndrome with lipomatosis

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  • CLOVES syndrome, Klippel-Trenaunay syndrome (KTW), Megalencephaly- CM (M-CM)[33],[34],[35],[36]
  • Macrodactyly, Dysplastic Megalencephaly, Fibroadipose Infiltrating Lipomatosis, Fibroadipose hyperplasia or Overgrowth, Hemihyperplasia Multiple Lipomatosis.

There are considerable overlaps among them and vascular malformation is one of the major components in M-CM, KTW, and CLOVE syndrome [Table 5].
Table 5: PIK3CA related overgrowth syndrome with wide clinical spectrum

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  Arteriovenous Malformations Top

AVMs are abnormal shunts between arteries and veins without a normal intervening capillary bed [Table 6].
Table 6: Isolated and syndromic arteriovenous malformations and fistulas

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They are high-flow vascular malformations that radiographically featured by a central nidus, a tangle of blood vessels where multiple direct AV communications exist. Both AVM and arteriovenous fistula (AVF) are fast-flow vascular malformations, but AVF consists of a single direct communication between an artery and a vein. AVF can be cured if this single communication can be obliterated. As AVM lacks the dampening effect of capillaries on the blood flow, the AVM can get progressively larger over time. Due to long-standing high blood pressure of arterial blood flow, these veins engorge, creating the risk of rupture and hemorrhage. AVM (most cutaneous AVM lesions are present at birth and grow in proportion to the body. It is often mistaken in early life as port-wine stain [Figure 7]a. The most common sites are the head and neck regions. They are typically warm to touch, with a pink-red CM and a palpable thrill or audible bruit. They may undergo rapid growth spurt in response to menarche, trauma, or pregnancy. While many AVMs remain asymptomatic for life, they can cause serious problems over time or when they occur inside vital organs, such as the brain and spinal cord. The majority are isolated, but some are associated with syndromes, such as CM-AVM, HHT, and PWS. Sporadic extracranial AVMs are associated with somatic mutations in the MAP2K1 gene that leads to activation of the RAS-MAPK signaling pathway, similar to RASA 1 mutations in CM-AVM and PWS.[37],[38] CM-AVM is an autosomal dominant vascular disorder that is caused by the loss of function mutations of the RASA 1 and EPHB4.[39] Characteristically, patients with CM-AVM exhibit variable penetrance with cutaneous CM alone or together with AVM. Approximately a third of the patients with RASA1 mutation has a fast flow lesion: a fistula, an AVM or Parkes–Weber syndrome. The observed intra and interfamilial phenotypic variability could be explained by the somatic second hit on a germline RASA 1 mutation that may occur during fetal development. The somatic second hit causing PWS with a major defect must occur at an early developmental stage, whereas the events of allelic loss causing the small CM occur later during intrauterine or postnatal life.
Figure 7: Types of arteriovenous malformations. (a) Capillary malformation with underlying arteriovenous malformations suggested by multiple peripheral halos and bier spots. (b) Multiple telangiectasia in hereditary hemorrhagic telangiectasia

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  Hereditary Hemorrhagic Telangiectasia Top

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder where patients are at risk of developing mucocutaneous telangiectasia (i.e., lips, oral cavity, nose, and fingers) [Figure 7]b and visceral AVFs/AVMs (i.e., pulmonary, cerebral, hepatic, GI). Recurrent epistaxis is the most common presenting problem, occurring in 90% of affected patient at some point in their life and tends to worsen with age. GI bleeding, which affects about one-third, does not present until the 4th decade of life or later. Many patients with HHT have iron-deficiency anemia caused by frequent epistaxis and GI bleeding. Genetically, mutations in endoglin or activating A receptor type 2-like 1 (ACVRL1/ALK1) are responsible for almost all cases. SMAD4 (associated with juvenile polyposis) or GDF2 mutations affect 2% of patients.[40],[41],[42]

  Conclusion Top

It is essential for the clinician to understand the genetic and molecular basis of vascular anomalies as this information will greatly influence its classification and future treatment options. New therapies target the implicated signaling pathway are only possible if the defective genes, proteins, and dysregulated pathways are identified [Figure 8]. Mutations associated with vascular malformations often occur in genes encoding proteins that are part of the RAS/MEK/ERK and/or PI3kinase/AKT/mTOR signaling pathways. Such genetic changes lead directly to altered endothelial cell proliferation, differentiation, and survival. In addition to sclerotherapy and surgical excision, inhibitors of proteins along the PI3K/AKT/mTOR or RAS/BRAF/MAPK/ERK pathways are emerging as targeted therapeutic options for different types of vascular malformations. Thus far, inhibitor of mTOR, AKT1, and PIK3CA (sirolimus, miransertib, and alpelisib) have promising clinical results.[43],[44],[45],[46]
Figure 8: Schematic diagram of molecular genetics and signalling pathways in endothelial cells associated to different types of vascular malformations

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Conflicts of interest

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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  In this article
Genetics of Vasc...
Mosaicism, Somat...
Capillary Malfor...
Venous Malformations
Common Venous Ma...
Common Venous Ma...
Familial Cutaneo...
Glomuvenous Malf...
Verrucous Venous...
Common Cystic Ly...
PIK3CA-Related O...
Arteriovenous Ma...
Hereditary Hemor...
Mosaicism, Somat...
Arteriovenous Ma...
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