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Multiple Cutaneous and Mucosal Venous Malformations

Synonym: VMCM1

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Center for Vascular Anomalies
Division of Plastic Surgery
Cliniques Universitaires St Luc &
Université catholique de Louvain
Brussels, Belgium
, MD, PhD
Laboratory of Human Molecular Genetics
de Duve Institute, Université catholique de Louvain
Brussels, Belgium

Initial Posting: ; Last Update: August 23, 2012.

Summary

Disease characteristics. The condition multiple cutaneous and mucosal venous malformations (VMCM) is characterized by the presence of small, multifocal bluish cutaneous and/or mucosal venous malformations. They are usually present at birth. New lesions appear with time. Small lesions are usually asymptomatic; larger lesions can invade subcutaneous muscle and cause pain. Malignant transformation has not been reported.

Diagnosis/testing. Diagnosis of VMCM is based on clinical evaluation of the cutaneous lesions. Doppler ultrasound examination and MRI can be used to confirm the venous component and extent of lesions. TEK (also known as TIE2) is the only gene in which mutations are known to cause VMCM.

Management. Treatment of manifestations: Sclerotherapy, alone or in combination with plastic and reconstructive surgery, is used depending on the size and location of the lesions. When D-dimers are elevated, low molecular-weight heparin can be used to treat the associated pain.

Prevention of secondary complications: If the D-dimer level is greater than twice the normal range, low molecular-weight heparin should be initiated before any surgery to avoid disseminated intravascular coagulopathy.

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

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

Genetic counseling. VMCM is inherited in an autosomal dominant manner. Most individuals diagnosed with VMCM have an affected parent; the proportion of cases caused by de novo mutations is unknown; none has been reported to date. Each child of an individual with VMCM has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the TEK disease-causing mutation of an affected family member has been identified.

Diagnosis

Clinical Diagnosis

The clinical diagnosis of multiple cutaneous and mucosal venous malformations (VMCM) is based on the presence of small, multifocal cutaneous and/or mucosal bluish-purple vascular lesions (Figure 1) [Wouters et al 2008, Dompmartin et al 2010, Boon et al 2011, Boon & Vikkula 2012]. They are soft and usually compressible.

Figure 1

Figure

Figure 1. Multifocal mucocutaneous venous malformations (marked by arrows): (A) on the tongue; (B) on the neck; (C) in the supraclavicular area (scar of a resected VMCM, arrow heads); (D) on the distal forearm/wrist

Doppler ultrasound examination can be used to confirm slow blood flow.

Ultrasound examination reveals saccular compressible venous-like cavities.

Testing

D-dimer concentration may be elevated in individuals with multifocal VMCM, whereas it is normal in individuals with multifocal glomuvenous malformations.

Molecular Genetic Testing

Gene. TEK (previously known as TIE2) is the only gene in which mutations are known to cause VMCM [Brouillard & Vikkula 2007, Wouters et al 2008].

Table 1. Summary of Molecular Genetic Testing Used in Multiple Cutaneous and Mucosal Venous Malformations

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
TEKSequence analysisSequence variants 2100%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants [Brouillard & Vikkula 2007, Wouters et al 2008] may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis is based on clinical evaluation and family history taken by an expert in the field. D-dimer measurement may help differentiate VMCM from other conditions. Doppler ultrasound is useful for the diagnosis of subcutaneous lesions. Identification of a pathogenic mutation in TEK using molecular genetic testing confirms the diagnosis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The most typical finding in multiple cutaneous and mucosal venous malformations (VMCM) is presence of small multifocal cutaneous and/or mucosal venous malformations of bluish color [Brouillard & Vikkula 2007, Boon & Vikkula 2012]. They are usually present at birth and grow commensurable with the child. New lesions appear with time.

Small lesions are usually asymptomatic, but can be of esthetic concern. They do not usually bleed or ulcerate. Larger lesions can invade subcutaneous muscle and cause pain.

The size, number, and localization of lesions vary within and between families. 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.

Malignant transformation of the vascular malformations has not been reported.

Histologic findings. Enlarged venous-like channels with walls of smooth muscle of variable thickness are observed [Vikkula et al 1996]. The endothelium is flattened but continuous. If rounded mural cells (glomus cells) are observed, the diagnosis is glomuvenous malformation [Brouillard et al 2008] (see Differential Diagnosis).

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been reported.

  • All mutations identified so far are located in the parts of the gene coding for the tyrosine kinase domains of the receptor.
  • Intra- and interfamilial variation in expression of the phenotype is wide.

Penetrance

Approximately 90% of individuals who have a mutation in TEK develop mucocutaneous venous malformations by age 20 years; conversely, approximately 10% of individuals with a TEK mutation are clinically unaffected [Boon et al 2004].

Anticipation

Anticipation is not observed.

Nomenclature

Terms used previously to describe venous malformation include “cavernous angioma” and sometimes “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 US.

Prevalence

The prevalence of VMCM is unknown; however, it accounts for 1% of individuals with venous anomalies followed in multidisciplinary centers specializing in vascular abnormalities [Boon et al 2004].

Differential Diagnosis

Glomuvenous malformations, like multiple cutaneous and mucosal venous malformations (VMCM), are multifocal, small cutaneous venous-like lesions, but they are not usually seen on mucous membranes. They have a cobblestone appearance [Boon et al 2004, Mallory et al 2006]. Glomuvenous malformations are deeper purple in color than VMCM, are painful on palpation, and are more superficial than venous malformations. Histologically, they are characterized by the presence of abnormal mural cells called “glomus cells.”

Glomuvenous malformations are caused by loss-of-function mutations in GLMN, the gene encoding the protein glomulin [Brouillard et al 2002, Brouillard et al 2005]. Inheritance is autosomal dominant although paradominant inheritance (i.e., disease caused by presence of a germline mutation and a somatic mutation) has been suggested [Brouillard et al 2002].

Blue rubber bleb nevus (BRBN) syndrome is characterized by small multifocal cutaneous and mucosal venous-like lesions. They are rubbery blebs, often round and hyperkeratotic. They are associated with gastrointestinal lesions that often cause bleeding and severe chronic anemia. BRBN occurs sporadically. The etiology is not known.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with multiple cutaneous and mucosal venous malformations (VMCM), the following evaluations are recommended:

Treatment of Manifestations

Management depends largely on the size and location of the lesions. Treatment is required for any symptomatic VMCM lesion. Although sclerotherapy is the treatment of choice, sclerosing agents are not specific and can lead to ulceration if the VMCM is mucosal or involves the epidermis [Hammer et al 2001, Dompmartin et al 2010, Boon et al 2011]. Surgery gives a consistently better result if it is performed after sclerotherapy.

If lesions are painful and D-dimers are elevated, low molecular-weight heparin can be used to alleviate pain [Dompmartin et al 2008].

Prevention of Secondary Complications

If VMCM is associated with localized intravascular coagulopathy (LIC) (D-dimer level greater than twice the normal range), treatment with low molecular-weight heparin should be initiated before any surgery in order to avoid perioperative decompensation of LIC into disseminated intravascular coagulopathy (DIC).

Surveillance

Because VMCM lesions can increase in size over time and become painful or symptomatic, affected individuals should be reevaluated yearly or whenever symptoms arise.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

Evaluating neonates at risk by physical examination is appropriate in order 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.

If the disease-causing TEK mutation 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 small new lesions; in addition, existing lesions may increase in size and become painful. If the D-dimer level is high, low molecular-weight heparin therapy may be used to alleviate pain.

Antenatal diagnosis of VMCM 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.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Multiple cutaneous and mucosal venous malformations (VMCM) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with multiple cutaneous and mucosal venous malformations have an affected parent.
  • A proband with multiple cutaneous and mucosal venous malformations may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown; to date none has been reported.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include careful dermatologic evaluation. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with VMCM have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) Somatic mosaicism for TEK mutations causes either multifocal, sporadic venous malformations or a single venous malformation [Limaye et al 2009].

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, the risk to the sibs is 50%.
  • Ten percent of individuals with a TEK mutation will not have findings of VMCM; therefore, when the parents of the proband are clinically unaffected the sibs of a proband may still be at risk.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

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

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Foundation for Faces of Children
    258 Harvard Street
    #367
    Brookline MA 02446-2904
    Phone: 617-355-8299
    Email: info@facesofchildren.org
  • National Organization of Vascular Anomalies (NOVA)
    PO Box 38216
    Greensboro NC 27438-8216
    Phone: 919-844-0370
    Email: admin@mail.novanews.org; admin@mail.novanews.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Multiple Cutaneous and Mucosal Venous Malformations: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TEK9p21​.2Angiopoietin-1 receptorTEK homepage - Mendelian genesTEK

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Multiple Cutaneous and Mucosal Venous Malformations (View All in OMIM)

600195VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL; VMCM
600221TEK TYROSINE KINASE, ENDOTHELIAL; TEK

Normal allelic variants. TEK has 24 exons.

Pathologic allelic variants. Only eight different pathologic variants have been reported (see Table 2; Table A, HGMD). The c.2545C>T substitution was detected in six families [Vikkula et al 1996, Wouters et al 2010, Boon et al 2011].

Paradominant inheritance (i.e., presence of a germline mutation and a somatic mutation) may be the mechanism of disease causation, as demonstrated by the somatic ‘second hit’ identified in one VMCM tissue [Limaye et al 2009].

Table 2. TEK Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2545C>Tp.Arg849TrpNM_000459​.3
NP_000450​.2
c.2690A>Cp.Tyr897Ser

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The normal gene product, TEK, is a dimeric receptor tyrosine kinase mostly expressed on vascular endothelial cells. TEK binds the ligands angiopoietin 1, 2, and 4. Its function is important for endothelial cell proliferation, survival, and migration during angiogenesis, and later for vascular stability.

Abnormal gene product. Mutant TEK has increased autophosphorylation (a gain-of-function mutation) and can activate STAT1 signaling, in contrast to wild-type TEK [Korpelainen et al 1999, Limaye et al 2009, Boon et al 2011]. A somatic second hit identified in one VMCM tissue is a loss-of-function mutation[ Limaye et al 2009].

References

Literature Cited

  1. Boon LM, Enjolras O, Mulliken JB, Vikkula M. Vascular malformations. In: Irvine A, Hoeger P, Yan A, eds. Harper’s Textbook of Pediatric Dermatology. 3 ed. Wiley-Blackwell; 2011:112.1-112.24.
  2. Boon LM, Mulliken JB, Enjolras O, Vikkula M. Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol. 2004;140:971–6. [PubMed: 15313813]
  3. Boon LM, Mulliken JB, Vikkula M, Watkins H, Seidman J, Olsen BR, Warman ML. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet. 1994;3:1583–7. [PubMed: 7833915]
  4. Boon LM, Vikkula M. Vascular anomalies. In: Fitzpatrick’s Dermatology in General Medicine. 8 ed. New York, NY: McGraw-Hill Professional Publishing; 2012.
  5. Brouillard P, Boon LM, Mulliken JB, Ghassibé M, Warman ML, Tan OT, Olsen BR, Vikkula M. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas"). Am J Hum Genet. 2002;70:866–74. [PMC free article: PMC379115] [PubMed: 11845407]
  6. Brouillard P, Enjolras E, Boon LM, Vikkula M. Glomulin and glomuvenous malformation. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. New York, NY: Oxford University Press; 2008.
  7. Brouillard P, Ghassibé M, Penington A, Boon LM, Dompmartin A, Temple IK, Cordisco M, Adams D, Piette F, Harper JI, Syed S, Boralevi F, Taïeb A, Danda S, Baselga E, Enjolras O, Mulliken JB, Vikkula M. J Med Genet. 2005;42:e13. [PMC free article: PMC1735996] [PubMed: 15689436]
  8. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet. 2007;16:R140–9. [PubMed: 17670762]
  9. Dompmartin A, Acher A, Dompmartin A, Acher A, Thibon P, Tourbach S, Hermans C, Deneys V, Pocock B, Lequerrec A, Labbé D, Barrellier M-T, Vanwijck R, Vikkula M, Boon LM. Association of localized intravascular coagulopathy with venous malformations. Arch Dermatol. 2008;144:873–7. [PubMed: 18645138]
  10. Dompmartin A, Vikkula M, Boon LM. Phlebology. 2010;25:224–35. [PMC free article: PMC3132084] [PubMed: 20870869]
  11. Hammer FD, Boon LM, Mathurin P, Vanwijck RR. Ethanol sclerotherapy of venous malformations: evaluation of systemic ethanol contamination. J Vasc Interv Radiol. 2001;12:595–600. [PubMed: 11340138]
  12. Korpelainen EI, Karkkainen M, Gunji Y, Vikkula M, Alitalo K. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene. 1999;18:1–8. [PubMed: 9926914]
  13. Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB, Eklund L, Boon LM, Vikkula M. Nat Genet. 2009;41:118–24. [PMC free article: PMC2670982] [PubMed: 19079259]
  14. Mallory SB, Enjolras O, Boon LM, Rogers E, Berk DR, Blei F, Baselga E, Ros AM, Vikkula M. Congenital plaque-type glomuvenous malformations presenting in childhood. Arch Dermatol. 2006;142:892–6. [PubMed: 16847206]
  15. Vikkula M, Boon LM, Carraway KL 3rd, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996;87:1181–90. [PubMed: 8980225]
  16. Wouters V, Boon LM, Vikkula M. TIE2 and cutaneomucosal venous malformation. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. New York, NY: Oxford University Press; 2008.
  17. Wouters V, Limaye N, Uebelhoer M, Irrthum A, Boon LM, Mulliken JB, Enjolras O, Baselga E, Berg J, Dompmartin A, Ivarsson SA, Kangesu L, Lacassie Y, Teebi AS, Pennington A, Rieu P, Vikkula M. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur J Hum Genet. 2010;18:414–20. [PMC free article: PMC2841708] [PubMed: 19888299]

Chapter Notes

Author Notes

Centre for Vascular Anomalies, Cliniques Universitaires St Luc
Dr. Vikkula’s Web page, de Duve Institute

Revision History

  • 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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