Clinical characteristics.

TEK-related venous malformations (VM) encompass a range of phenotypes. Following the International Society for the Study of Vascular Anomalies (ISSVA) classification, these include common VM (unifocal/isolated VM or multifocal sporadic VM [MSVM]), multiple cutaneous and mucosal VM (VMCM), and blue rubber bleb nevus (BRBN) syndrome. VM are usually present at birth and grow with time, and new lesions can appear over time in individuals with MSVM, VMCM, and BRBN syndrome. Small lesions are usually asymptomatic; larger lesions can extend into other tissues, including subcutaneous tissues and muscles, causing pain and functional limitations. Malignant transformation has not been reported in TEK-related VM to date.

Diagnosis/testing.

The diagnosis of TEK-related VM is established in a proband with suggestive findings and either a heterozygous germline gain-of-function pathogenic variant (VMCM) or a somatic (mosaic) gain-of-function pathogenic variant (unifocal VM, MSVM, BRBN syndrome) identified by molecular genetic testing.

Management.

Treatment of manifestations: Sclerotherapy, alone or in combination with plastic and reconstructive surgery, depending on the size and location of the lesions. Low-molecular-weight heparin (LMWH) should be administered prior to any invasive procedure (sclerotherapy and/or surgery) to avoid disseminated intravascular coagulopathy. If D-dimers are elevated and fibrinogen levels are low, LMWH should be initiated one to two weeks before surgery, depending on severity of coagulation abnormality, and continued for two weeks after surgery. If fibrinogen levels are normal, LMWH can be initiated the day before surgery. If lesions are painful and D-dimers are elevated, LMWH can also be used to treat the associated pain. For gastrointestinal VM, endoscopic evaluations with abdominal imaging are needed. Sirolimus has been recently used with some success in individuals with TEK-related VM who do not respond to or are ineligible for surgery or sclerotherapy, and has been shown to reduce pain and functional complications.

Surveillance: Clinical reevaluation of TEK-related VM lesions annually and if symptoms arise. D-dimer levels should be measured every five years, if lesions become painful, and before any surgical and/or sclerotherapeutic procedure. Individuals on sirolimus should be closely followed at the beginning and throughout the course of their treatment, in order to modify the dosage as well as manage adverse events.

Agents/circumstances to avoid: Contraceptive pills with high estrogen concentration.

Evaluation of relatives at risk: Physical examination of at-risk neonates to identify those who can benefit from early treatment.

Pregnancy management: D-dimer levels should be evaluated every one to three months during pregnancy (depending on the symptoms) and prior to delivery to adjust LMWH therapy and to avoid abnormal bleeding during delivery.

Genetic counseling.

TEK-related VM are either inherited in an autosomal dominant fashion (TEK-related VMCM) or caused by somatic (mosaic) variants (TEK-related unifocal VM, MSVM, and BRBN syndrome).

For TEK-related VMCM, most individuals have an affected parent. The proportion of cases caused by a de novo pathogenic variant is unknown; none have been reported to date. In some affected individuals, lesions are small. Therefore, careful skin examination is needed in order to determine if a family member is affected. Each child of an individual with TEK-related VMCM has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the TEK pathogenic variant has been identified in an affected family member.

With regards to other TEK-related phenotypes, unifocal VM, MSVM, and BRBN syndrome are not known to be inherited, as identified pathogenic variants to date are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date. The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in TEK would be expected to be the same as in the general population. Due to mosaicism, the risk for transmission to offspring is expected to be less than 50%.

Suggestive Findings

TEK-related VM should be suspected in a proband with the following clinical features, laboratory findings, and family history.

Clinical Features

Cutaneous and/or mucosal bluish-purple VM can be either single or multiple, and can vary in size from a few millimeters in diameter to larger lesions affecting an entire extremity (see Figure 1 and Figure 2).

Figure 1.

Multiple cutaneous and mucosal venous malformations (VMCM) (marked by arrows) in one affected individual A. On the tongue

Figure 2.

Various venous malformations (VM) Common sporadic VM of the arm (A); multifocal sporadic VM (MSVM) of the hand and forearm (B); in blue rubber bleb nevus (BRBN) syndrome, large "dominant" congenital VM of the buttock seen on MRI (C); multiple small and (more...)

• Lesions are soft and usually compressible.
• Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.

In multiple cutaneous and mucosal VM (VMCM), multifocal sporadic VM (MSVM), and unifocal/isolated VM, lesions are predominantly cutaneous and mucosal, and rarely internal.

In blue rubber bleb nevus (BRBN) syndrome, affected individuals are often born with a large so-called dominant lesion, and numerous cutaneous and internal VM develop with time, with a predilection for the palms and soles. The VM in BRBN syndrome have a rubbery consistency with hyperkeratosis. Gastrointestinal lesions cause bleeding, iron deficiency, and intestinal complications (volvulus and infarction). Gastrointestinal VM are considered pathognomonic of BRBN syndrome.

Establishing the Diagnosis

The diagnosis of TEK-related VM is established in a proband with suggestive findings and a heterozygous germline pathogenic (or likely pathogenic) variant in TEK (TEK-related VMCM) or a somatic pathogenic (or likely pathogenic) variant in TEK (unifocal VM, MSVM, and BRBN syndrome) identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this section is understood to include any likely pathogenic variant. (2) Identification of a TEK variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

As many TEK pathogenic variants are postzygotic (or mosaic), deep sequencing as well as testing more than one tissue sample may need to be considered in the diagnostic workup of an affected individual.

Given the possibility of mosaicism, the following are considerations for molecular testing and sample selection:

• Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from the vascular lesion, requiring a surgical or skin biopsy ‒ should be prioritized for genetic testing.
• The level of mosaicism for an activating TEK variant in affected tissues or cultured cells is highly variable. Variant allele fractions can be as low as 1% in some individuals.
• Testing peripheral blood or DNA isolated from blood alone is only recommended when a clear family history is present suggesting the diagnosis of TEK-related VMCM. In other instances, and as TEK pathogenic variants are often mosaic, testing vascular tissue is usually more helpful.

Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other (inherited) disorders with vascular malformations are more likely to be diagnosed using genomic testing, if an appropriate sample is used (see Option 2).

Note: On analysis of DNA derived from affected tissues, the method used for testing must be sensitive enough to detect low-level mosaicism of a pathogenic variant (see Molecular Pathogenesis).

Clinical Description

TEK-related venous malformations (VM) encompass several phenotypes including isolated (or unifocal) VM, multifocal sporadic VM (MSVM), multiple cutaneous and mucosal VM (VMCM), and blue rubber bleb nevus (BRBN) syndrome.

Genotype-Phenotype Correlations

The phenotypic spectrum of individuals with somatic pathogenic variants in TEK is broader than in individuals with germline pathogenic variants in TEK, as somatic mosaicism implies that the percentage, type, and location of cells affected by a pathogenic variant vary between affected individuals.

Some TEK pathogenic variants are more likely to be associated with a specific subtype of TEK-related VM. For example, c.2545C>T (p.Arg849Trp) is the most common variant detected in TEK-related VMCM, while c.2740C>T (p.Leu914Phe) is the most common variant detected in TEK-related unifocal VM and has not been observed in VMCM, MSVM, or BRBN syndrome [Vikkula et al 1996, Wouters et al 2010, Boon et al 2011a].

See the Molecular Pathogenesis section for information regarding types of genetic variants seen in different types of TEK-related venous malformations.

Penetrance

Approximately 90% of individuals who have a germline pathogenic gain-of-function variant in TEK (TEK-related VMCM) develop mucocutaneous VM by age 20 years; conversely, approximately 10% of individuals with a germline pathogenic gain-of-function variant in TEK are clinically unaffected [Boon et al 2004, Wouters et al 2010]. Reduced penetrance can be explained by the need to acquire a second, somatic pathogenic gain-of-function variant either in the normal allele or the allele with the pathogenic variant, or loss of the normal allele, in the target cell(s) in order to develop a lesion(s) [Limaye et al 2009, Soblet et al 2017].

The penetrance of other TEK-related phenotypes (unifocal VM, MSVM, BRBN syndrome) is currently unknown. It is hard to estimate, as many TEK pathogenic variants may elude detection due to mosaicism. Data suggest that pathogenic variants in TEK are sufficient to cause the phenotype, but some individuals with pathogenic variants in more than one gene (e.g., TEK and PIK3CA) have been described [M Vikkula, personal communication].

Nomenclature

The title of this GeneReview, TEK-related venous malformations (VM), is based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders. Therefore, this term encompasses all known TEK-related VM phenotypes reported to date, including multiple cutaneous and mucosal VM (VMCM), multifocal sporadic VM (MSVM), unifocal (isolated) VM, and blue rubber bleb nevus (BRBN) syndrome.

Terms used previously to describe VM include "cavernous angioma" and "cavernous hemangioma." The term "mucocutaneous venous malformation" was coined by Boon et al [1994] for the lesions identified in a large multigenerational family from the United States in which the TEK locus was first identified.

Prevalence

VM are often considered the most common subtype of vascular malformations seen in specialty clinics, with an incidence between 1:2,000 and 1:5,000 live births. More than 90% of VM are sporadic and isolated [Wassef et al 2015].

Although unknown, the prevalence of TEK-related VM, such as MSVM, VMCM and BRBN syndrome, remains much lower than sporadic unifocal VM; VMCM is estimated to account for fewer than 1% of individuals with venous anomalies followed in multidisciplinary centers specializing in vascular anomalies [Boon et al 2004]. BRBN syndrome is rarely reported, with around 250 individuals reported to date [Soblet et al 2017]. The low incidence of these phenotypes could be due to their rarity or underdiagnosis.

Evaluations Following Initial Diagnosis

To establish the extent of disease and management needs in an individual diagnosed with TEK-related VM, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is required for any symptomatic VM. Management depends largely on the size and location of the lesions. Small lesions can be surgically resected or treated with sclerotherapy with very favorable outcomes (often complete cure). However, in many instances complete resection or embolization is not possible.

If affected individuals are asymptomatic, with no lesion that may cause severe or life-threatening complications (e.g., medullary compression, pathologic bone fracture, airway compression), it is preferable to delay any therapeutic intervention and clinically monitor the individual over time.

Treatment of TEK-related VM ideally involves multidisciplinary care by specialists in vascular anomalies, interventional radiology, surgery, oncology, hematology, and genetics (see Table 5).

Surveillance

To monitor existing manifestations of TEK-related VM, the individual's response to treatment, and the emergence of new manifestations, the evaluations in Table 7 are recommended.

For individuals on MTOR inhibitor therapy such as sirolimus, a targeted off-label therapy, several surveillance guidelines are recommended (see Table 8).

Agents/Circumstances to Avoid

Contraceptive pills with high estrogen concentration should be avoided, as VM are estrogen responsive. VM can increase in size and become symptomatic, especially at the initiation of estrogen-based contraception. In some but not all instances stabilization of a VM lesion and diminution of pain may be observed after three months of contraceptive pill use.

Evaluation of Relatives at Risk

Relatives of a proband with inherited TEK-related VM or VMCM. Evaluating at-risk neonates by physical examination is appropriate to identify those who may benefit from early treatment.

Lesions arising after infancy usually stay small and therefore are rarely symptomatic. If no lesions are seen at birth, a second evaluation should be done around puberty.

Once a germline TEK pathogenic variant has been identified in the family, molecular genetic testing can be used to evaluate at-risk relatives.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

During pregnancy, affected women may develop new small lesions; in addition, existing lesions may increase in size and become painful.

If D-dimer levels are high, low-molecular-weight heparin may be used to alleviate pain.

D-dimer levels should be evaluated every one to three months during pregnancy depending on the symptoms and before delivery to adjust medication and avoid abnormal bleeding during delivery.

In individuals on sirolimus, avoiding pregnancy and lactation is recommended, as this drug is classified as an FDA category C drug in pregnancy and lactation.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

In recent years, multiple trials have reported on the efficacy of MTOR inhibitors in the treatment of slow-flow vascular malformations. A pilot study on rapamycin therapy for venous malformations (VM) reported beneficial results, especially regarding pain reduction and improvement in quality of life [Boscolo et al 2015]. Several Phase II trials showed improvement in symptoms such as pain, bleeding, and functional limitation and improvement in quality of life [Boscolo et al 2015, Adams et al 2016, Hammer et al 2018, Ji et al 2021, Maruani et al 2021].

A prospective multicentric Phase III trial (VASE) is currently evaluating the efficacy and safety of sirolimus in slow-flow vascular anomalies that are refractory to standard care (NCT02638389). This study started in January 2016 and has enrolled the intended 250 patients (as of January 2023). In the VASE trial, enrolled individuals receive sirolimus for two years at a starting daily dose of 2 mg for adults and 0.8 mg/m² twice daily for children younger than age 18 years. Individuals are evaluated every month for three months and then every three months for the treatment duration. Sirolimus is discontinued after two years and can be reintroduced in case of symptom recurrence. Preliminary results from the first 132 enrolled individuals (including 76 with VM) who were followed for at least 12 months showed that 87% of had less pain and functional limitation [Seront et al, unpublished data].

Adverse events were frequent, occurring in 96% of individuals receiving sirolimus therapy, but were most commonly mild, with the majority being grade 1 and 2 in severity and thus easily manageable. The most common toxicities were asthenia (70% grade 1-2, 4% grade 3-4), mucositis (66% grade 1-2, 8% grade 3-4), diarrhea (40% grade 1-2, 2% grade 3-4), headache (25% grade 1-2, 5% grade 3-4), cutaneous rash (31% grade 1-2, 1% grade 3-4), and pyrosis (21% grade 1-2, 0% grade 3-4). These results are consistent with other previous reports, highlighting the efficacy and safety of sirolimus in VM [Seront et al, unpublished data]. Sirolimus has also shown to improve gastrointestinal bleeding in BRBN syndrome, with fast recovery of hemoglobin levels, and is currently considered the best therapeutic option when there is multiorgan involvement in BRBN syndrome [Zhou et al 2021].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

TEK-related venous malformations (VM) include:

• The autosomal dominant disorder multiple cutaneous and mucosal venous malformations (VMCM), caused by germline heterozygous TEK pathogenic variants;
• The sporadic (or mosaic) disorders unifocal/isolated VM, multifocal sporadic VM (MSVM), and blue rubber bleb nevus (BRBN) syndrome, caused by postzygotic (mosaic) TEK pathogenic variants.

Molecular genetic testing of leukocyte DNA from the proband is necessary to distinguish between these categories of TEK-related VM and to establish reliable recurrence risk.

VMCM – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with VMCM have an affected parent.
• To date, VMCM caused by a de novo germline TEK pathogenic variant has not been reported.
• If the proband appears to be the only affected family member (i.e., neither parent of the proband has clinical evidence of VMCM on dermatologic evaluation), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with VMCM may appear to be negative because of a milder phenotypic presentation, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the TEK pathogenic variant that was identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or known to have the TEK pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in TEK develop mucocutaneous venous malformations by age 20 years (see Penetrance).
  • The size, number, and localization of lesions vary between family members with the same TEK pathogenic variant. Often one individual in a family has more extensive lesions than other family members; conversely, some family members may have only a few small, clinically insignificant lesions.
• If the TEK pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to the sibs is estimated to be 1% because of the theoretical possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the TEK pathogenic variant but are clinically unaffected, sibs of a proband are still at increased risk for VMCM because of the possibility of reduced penetrance in a parent (10% of individuals with a TEK pathogenic variant will not have findings of VMCM) and the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with VMCM has a 50% chance of inheriting the TEK pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TEK pathogenic variant, the parent's family members may be at risk.

Unifocal VM, MSVM, and BRBN Syndrome – Risk to Family Members

Parents of a proband. Parents of children with a postzygotic (mosaic) TEK pathogenic variant(s) have not been reported to have any significant distinctive manifestations of the disorder, nor would such findings be expected given the somatic nature of these genetic alterations.

Sibs of a proband. Given the somatic mutational mechanism of TEK-related unifocal VM, MSVM, and BRBN syndrome, the risk for an affected sib would be expected to be the same as in the general population.

Offspring of a proband. There are no instances of vertical transmission of TEK-related unifocal VM, MSVM, or BRBN syndrome.

Other family members. The risk to other family members is the same as that in the general population.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives of a proband with TEK-related VMCM for the purpose of early diagnosis and treatment.

Considerations in families with an apparent postzygotic (mosaic)TEK pathogenic variant(s). Counseling for recurrence risk in TEK-related unifocal VM, MSVM, and BRBN syndrome should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk of recurrence for these disorders is not increased compared to the general population.

Family planning

• The optimal time for determination of genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

VMCM

• Molecular genetic testing. Once a germline heterozygous TEK pathogenic variant has been identified in a family member with VMCM, prenatal and preimplantation genetic testing are possible.
• Imaging studies. Prenatal diagnosis of VMCM using imaging studies such as Doppler ultrasonography and/or MRI has not been reported. The number and size of fetal lesions are variable and unpredictable. Doppler ultrasonography may be used to evaluate for fetal lesions in those fetuses at increased risk for VMCM, but the small size of the lesions makes them difficult to detect.

Unifocal VM, MSVM, and BRBN syndrome. As these disorders are not inherited, prenatal testing is not indicated.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TEK encodes the angiopoietin-1 receptor (TIE2), a dimeric receptor tyrosine kinase mostly expressed on vascular endothelial cells. TIE2 binds the ligands angiopoietin 1, 2, and 4. Binding of growth factors, such as angiopoietin 1 (ANGPT1), results in TIE2 phosphorylation, which leads to activation of the canonical phosphatidylinositol-3 kinase (PI3K) / protein B (AKT) / mammalian target of rapamycin (mTOR) signaling pathway. Its function is important for endothelial cell proliferation, survival, and migration during angiogenesis, and later for vascular stability.

Most TEK pathogenic variants associated with venous malformations (VM) are located within the kinase domain and cause a gain of function that in turn causes ligand-independent increased phosphorylation, activating the PI3K-AKT-FOXO1 pathway and leading to reduced PDGF-beta production [Uebelhoer et al 2013]. STAT1 signaling is also activated [Korpelainen et al 1999, Limaye et al 2009, Boon et al 2011b]. Loss of the normal allele at the cellular level (i.e., presence of a germline gain-of-function pathogenic variant on one allele and an acquired somatic pathogenic event on the other allele) may be the mechanism of disease in TEK-related multiple cutaneous and mucosal VM (VMCM), as demonstrated by the somatic "second hit" identified in one VMCM tissue [Limaye et al 2009, Soblet et al 2017]. Other TEK-associated phenotypes, including multifocal sporadic VM (MSVM), unifocal VM, and blue rubber bleb nevus (BRBN) syndrome are caused by mosaic variants in TEK (see Table 9). While sporadic or isolated VM need only one variant to develop, MSVM and BRBN syndrome most often contain two somatic variants in TEK.

Although all VM-associated TEK pathogenic variants result in ligand-independent phosphorylation of TIE2, the levels of hyperphosphylation of germline and somatic variants are variable [Wouters et al 2010], which may contribute to the significant intra- and interfamilial variability. Uebelhoer et al [2013] and Nätynki et al [2015] have reported that TIE2 phosphorylation, localization, trafficking, and cellular phenotype differ by variant type.

Gain-of-function mutations in TEK are detected in the majority of sporadically occurring unifocal and multifocal VM (unifocal VM and MSVM, respectively) and in BRBN syndrome, as well as in inherited VMCM (see GeneReview Scope).

Mechanism of disease causation. Gain of function

TEK-specific laboratory technical considerations. Both germline and mosaic variants are seen in TEK-related VM. Mosaic genetic variants in TEK can have low variant allele fractions and therefore elude detection using standard sequencing methods. Using sequencing methods with a higher depth of coverage for the detection of pathogenic TEK variants is recommended.

Author Notes

Center for Vascular Anomalies, Cliniques Universitaires St Luc, Brussels, Belgium
Coordinator: Prof Laurence M Boon, plastic surgeon

VASCERN-VASCA
Co-Chairs: Profs Miikka Vikkula and Laurence M Boon

Prof Vikkula, de Duve Institute, Clinical Geneticist, WELBIO Investigator at the WEL Research Institute

Google Scholar profile (M Vikkula)

Google Scholar profile (L Boon)

Prof Miikka Vikkula, MD, PhD (1992-1993, Helsinki, Finland), is a professor of genetics who became interested in vascular anomalies during his postdoctoral training at Harvard Medical School (1993-1997). Together with his wife, Prof Laurence M Boon, MD, PhD, Coordinator of the Center for Vascular Anomalies (Brussels), he has unraveled some key concepts in the pathophysiology of vascular anomalies. The couple discovered TIE2 for familial venous malformation (in 1996), as well as many other genes since, and have demonstrated "second hits" in multiple cutaneous and mucosal venous malformations (VMCM) and glomuvenous malformations, identified novel clinical entities (such as CM-AVM1 and 2) and made the pivotal demonstration that somatic mutations explain sporadically occurring vascular anomalies (in 2009). With collaborative efforts to generate the first ever animal model for venous malformations, and the proof of concept for treatment with rapamycin, a small molecular inhibitor of VM, the couple is at the forefront of developing novel targeted therapies based on genetic and pathophysiologic discoveries. Clinical trials are now being conducted with various molecules in some countries. Moreover, off-label use of sirolimus has become a reference treatment for VM. Profs Boon and Vikkula are well-known internationally as major contributors to the understanding of the molecular basis of vascular anomalies, with >200 peer-reviewed publications, >50 reviews and chapters in major medical textbooks, and with >14,000 citations and an H-index of 59 (Google Scholar) for Prof Boon, and >23,000 citations and an H-index of 77 (Google Scholar) for Prof Vikkula. They have received numerous honors such as the Inbev-Baillet Latour Clinical Prize and, for Prof Vikkula, the 1st Generet Award 1 MEUR (in 2019). Prof Vikkula is also the recipient of the Earl Benditt Award 2023 by NAVBO (North American Vascular Biology Organization). They are both Full Members of the Royal Belgian Academy of Medicine. Prof Vikkula is also a WELBIO Investigator at the WEL Research Institute.

Dr Emmanuel Seront, MD, PhD (2013) is a medical oncologist who focused his PhD thesis on the mTOR signaling pathway in urologic cancers. He has since worked in close collaboration with the Boon-Vikkula team in order to conduct the large Phase III clinical trial (VASE) using sirolimus in slow-flow vascular malformations. Other trials evaluating new targeted agents are currently ongoing, based on genetic and pathophysiologic discoveries. Dr Seront is a member of the multidisciplinary Center for Vascular Anomalies, Brussels, Belgium (a VASCERN-VASCA reference center) and many oncologic societies (Belgian Society of Medical Oncology, European Society of Medical Oncology, American Society of Clinical Oncology).

All authors are actively involved in clinical research regarding individuals with TEK-related VMCM. They would be happy to communicate with persons who have any questions regarding diagnosis of TEK-related VMCM or other considerations.

Contact Prof Miikka Vikkula to inquire about TEK variants of uncertain significance.

All authors are also interested in hearing from clinicians treating families affected by VMCM in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Acknowledgments

All three authors of this publication are members of the Vascular Anomaly Working Group (VASCA) of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), Project ID: 769036.

We are grateful to all the affected individuals and their family members for their invaluable participation during the years of our research studies. Our studies have been financially supported by the Fonds de la Recherche Scientifique – FNRS Grants, most recently by T.0026.14 and T.0247.19 (to MV), T.0146.16 and P.C013.20 (to LMB), the Fund Generet managed by the King Baudouin Foundation (Grant 2018-J1810250-211305) (to MV), and by the Walloon Region through the FRFS-WELBIO strategic research program (WELBIO-CR-2019C-06) (to MV). Our work has also been funded by the MSCA-ITN network VA Cure No 814316 (to MV), the Lymphatic Malformation Institute (LMI), USA (to MV), and the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR Grant 21CVD03). Our groups have also been funded by the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694 (LB/MV), and by a continued Pierre M fellowship. We also thank the National Lottery, Belgium, and the Foundation against Cancer (2010-101), Belgium, for their support to the Genomics Platform of Université catholique de Louvain and de Duve Institute, as well as the Fonds de la Recherche Scientifique – FNRS Eguipment Grant U.N035.17 for the "Big Data Analysis Cluster for NGS at UCLouvain."

Revision History

• 2 March 2023 (gm) Comprehensive update posted live
• 17 May 2018 (ma) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 23 August 2012 (me) Comprehensive update posted live
• 18 September 2008 (me) Review posted live
• 17 January 2008 (mv) Original submission

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