Summary
Clinical 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.
The diagnosis of VMCM is established in a proband with small, multifocal cutaneous and/or mucosal bluish-purple vascular malformations with slow blood flow on Doppler ultrasound AND/OR by the identification of a heterozygous gain-of-abnormal-function pathogenic variant in TEK by molecular genetic testing.
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. Low molecular-weight heparin (LMWH) should be administered prior to any invasive procedure. When the D-dimer level is elevated and the fibrinogen level is low, LMWH should be initiated one to two weeks before surgery and continued for two weeks post surgery; if the fibrinogen level is normal, LMWH can be initiated the day prior to surgery. If the lesions are painful and D-dimers are elevated, LMWH can also be used to treat the associated pain.
Prevention of secondary complications: If the D-dimer level is greater than twice the normal range, LMWH should be initiated before any surgery to avoid disseminated intravascular coagulopathy.
Surveillance: Clinical reevaluation of VMCM 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.
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 before delivery to adjust heparin therapy and to avoid abnormal bleeding during delivery.
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 a de novo pathogenic variant is unknown; none has been reported to date. Each child of an individual with 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.
Diagnosis
Suggestive Findings
Multiple cutaneous and mucosal venous malformations (VMCM) should be suspected in individuals with the following clinical features, laboratory findings, and family history.
Clinical features. Small, multifocal cutaneous and/or mucosal bluish-purple vascular malformations (see ):
Multifocal mucocutaneous venous malformations (marked by arrows) A. On the tongue
Laboratory findings
D-dimer level is commonly elevated, in some cases three times the normal (i.e., <500 ng/mL) level.
Fibrinogen level can be below the normal (i.e., 150-450 ng/mL) range in cases of severe chronic consumptive coagulopathy.
Family history. Consistent with autosomal dominant inheritance. Note: Lack of a known family history of VMCM does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of VMCM is established in a proband:
Note: Biopsy is usually not necessary for diagnosis
Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:
Single-gene testing. Sequence analysis of
TEK is performed.
Note: Because VMCM occurs through a gain-of-abnormal-function mechanism and gross deletions/duplications predicted to result in a loss of function have not been reported,
gene-targeted
deletion/duplication analysis is not indicated.
A multigene panel that includes
TEK and other genes of interest (see
Differential Diagnosis) may be considered [
Limaye et al 2015]. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Table 1.
Molecular Genetic Testing Used in Multiple Cutaneous and Mucosal Venous Malformations
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| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|
|
TEK
| Sequence analysis 3, 4 | ~90% 5 |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
- 5.
Clinical Characteristics
Clinical Description
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 [Wouters et al 2008, Dompmartin et al 2010, Wouters et al 2010, Boon et al 2011, Boon & Vikkula 2012, Boon & Vikkula 2013]. They are usually present at birth and increase in size as the affected child grows. New lesions appear with time. The malformations range in size from 1 mm to 1 cm.
Small millimetric lesions are usually asymptomatic, but can be of aesthetic concern. They do not usually bleed or ulcerate. Larger lesions (up to a few centimeters in diameter) can invade subcutaneous muscles 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 (see Genotype-Phenotype Correlations). Lesions are randomly located throughout the body. In rare cases, they can affect the gastrointestinal and/or anal mucosa (in contrast to the oral mucosa, which is more typically affected) [Vikkula et al 1996, Brouillard & Vikkula 2007, Wouters et al 2010, Boon & Vikkula 2012].
Malignant transformation of the vascular malformations has not been reported.
D-dimer concentration. More than 80% of individuals with multifocal VMCM have elevated D-dimer concentration (normal: <500 ng/mL) [Dompmartin et al 2008, Dompmartin et al 2010, Wouters et al 2010, Boon et al 2011]. D-dimer concentration is elevated in about 40% of individuals with sporadic VM and is normal in more than 95% of individuals with multifocal glomuvenous malformations (see Differential Diagnosis) [Dompmartin et al 2008].
This coagulopathy is clinically asymptomatic unless the affected individual undergoes an intervention, such as a surgical procedure or sclerotherapy. If D-dimer concentration is higher than twice the normal range, excess pre- and/or postoperative bleeding is observed; it can be prevented by preoperative administration of low molecular weight heparin (LMWH).
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 [Boon et al 2004, Brouillard et al 2005, Brouillard et al 2008, Brouillard et al 2013] (see Differential Diagnosis).
Penetrance
Approximately 90% of individuals who have a germline pathogenic gain-of-abnormal-function variant in TEK develop mucocutaneous venous malformations by age 20 years; conversely, approximately 10% of individuals with a germline gain-of-abnormal-function TEK pathogenic variant 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-abnormal-function variant in the wild type or the already mutated TEK allele in the target cell(s) to develop a lesion(s) [Limaye et al 2009, Soblet et al 2017].
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.
The abbreviation VMCM stands for inherited venous malformation cutaneous and mucosal.
Prevalence
The prevalence of VMCM is unknown; however, it accounts for fewer than 1% of individuals with venous anomalies followed in multidisciplinary centers specializing in vascular abnormalities [Boon et al 2004].
VMCM and other TEK-mediated venous malformation disorders described below cover a spectrum of phenotypes of varying severity and models of mutation acquisition (reviewed by Soblet et al [2017]). Each disorder is caused by gain-of-abnormal-function pathogenic variants that result in varying degrees of ligand-independent activation (constitutive activation) of TIE2, the protein product of TEK (see Molecular Genetics). However, predisposition to the conditions listed below is not heritable because these variants are not present in the germline.
Blue rubber bleb nevus (BRBN) syndrome (OMIM 112200) is characterized by small multifocal cutaneous and mucosal venous-like lesions. They are rubbery blebs, often round and hyperkeratotic. There is often one large venous malformation (VM) lesion ("dominant lesion") at birth with subsequent development of multiple small rubbery bluish palmar and plantar lesions. Multiple gastrointestinal VMs may also develop and can cause bleeding and severe chronic anemia. The BRBN phenotype evolves much more over time than multifocal venous malformations (MVM) or VMCM. BRBN occurs sporadically.
BRBN is caused by somatic activating (gain-of-abnormal-function) pathogenic TEK variants [Soblet et al 2017]; thus, they typically are not detectable in DNA from blood cells unless highly sensitive molecular techniques are used. Unlike VMCM-causing pathogenic variants, they typically occur on the same allele (i.e., double [cis] pathogenic variants [>83%]). The allele NM_000459.4: c.[3314C>A;3316A>C], NP_000450.2:p.[(Thr1105Asn;Thr1106Pro)] is recurrent (57% of individuals with molecularly confirmed BRBN syndrome); the published nomenclature of the allele is T1105N-T1106P [Soblet et al 2017]. The remainder are largely double (cis) pathogenic variants containing NM_000459.4:c.2690A>G (p.Tyr897Cys) with different combinations [Soblet et al 2013, Soblet et al 2017]. Interestingly, the same double (cis) pathogenic variants are seen in multiple lesions from the same individual, suggesting a common cellular ancestor for the lesions.
Multifocal venous malformation (MVM), like VMCM, is characterized by multiple VMs all over the body, more commonly located on the skin, but (unlike BRBN) not on the palms and soles. Affected individuals can sometimes have gastrointestinal lesions. The VMs are often more subcutaneous than cutaneous. Individuals with MVM typically have fewer lesions than individuals with BRBN.
MVM is a sporadic condition. Like BRBN, it is caused by double (cis) pathogenic variants that occur on the same allele [Soblet et al 2017]. However, the affected individual typically acquires an initial mosaic activating pathogenic TEK variant (most commonly NM_000459.4: c.2743C>T (p.Arg915Cys) and subsequently acquires a second activating pathogenic variant on the same allele (most commonly NM_000459.4:c.2690A>G (p.Tyr897Cys), a so-called "second hit." The second-hit pathogenic variant may vary among lesions from the same individual. The haplotype of a pathogenic allele with the two most common variants would be designated as NM_000459.4:c.[2743C>T;2690A>G].
Venous malformation (VM) is the most common type of venous anomaly. This unifocal vascular malformation occurs sporadically. In about 60% of affected individuals, isolated VM is caused by somatic pathogenic variants in TEK; the most common is an NM_000459.4: c.2740C>T (p.Leu914Phe) variant on one allele [Limaye et al 2009, Soblet et al 2013]. Somatic heterozygosity for this allele appears to provide sufficient gain-of-abnormal-function activity for lesion formation. For other causes of unifocal venous malformation, see Differential Diagnosis.
Differential Diagnosis
Glomuvenous malformations (OMIM 138000), like multiple cutaneous and mucosal venous malformations (VMCM), are inherited 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, Brouillard et al 2013]. Glomuvenous malformations are deeper purple in color than VMCM, are painful on palpation, and are less invasive than sporadic venous malformations. Most lesions are located on the extremities. Histologically, they are characterized by the presence of abnormal mural cells called "glomus cells."
Glomuvenous malformations are caused by heterozygous loss-of-function pathogenic variants in GLMN (encoding glomulin). Inheritance is autosomal dominant, although the pathophysiologic mechanism is recessive at the cellular level (i.e., disease caused by presence of a germline pathogenic variant on one allele and an acquired somatic pathogenic variant on the other allele), most frequently as a result of an acquired uniparental isodisomy [Brouillard et al 2002, Amyere et al 2013].
Venous malformation (VM) is caused by somatic heterozygous pathogenic PIK3CA variants in about 20% of affected individuals. Like TEK variants, these PIK3CA variants are gain-of-abnormal-function (activating) variants that result in constitutive activation of the downstream PI3K/AKT signaling pathway [Limaye et al 2015]. See Genetically Related Disorders.
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 if they have not already been completed:
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]. Foam aethoxysclerol and bleomycin are preferentially used as sclerosing agents.
Surgery is effective for small lesions. For large VMs, surgical resection gives a better result if it is performed after sclerotherapy. Before any invasive procedure (i.e., surgery and/or sclerotherapy), low molecular weight heparin (LMWH) should be administered to reduce the bleeding risk. In the presence of an elevated D-dimer level and a low fibrinogen level, LMWH should be initiated one or two weeks before surgery, depending on the severity of the coagulation abnormality, and continued for two weeks after surgery. If the fibrinogen level is normal, LMWH can be initiated the day before surgery.
If lesions are painful and D-dimers are elevated, LMWH can be used to alleviate pain [Dompmartin et al 2008]. Moreover, D-dimer levels can be used to evaluate the efficacy of both sclerotherapy and LMWH treatments, as levels will decrease with the lesion.
Prevention of Secondary Complications
If VMCM is associated with localized intravascular coagulopathy (LIC) (i.e., D-dimer level >2x 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.
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.
Measurements of serum D-dimers should be performed:
Agents/Circumstances to Avoid
Contraceptive pills with high estrogen concentration should be avoided, as venous malformation lesions are estrogen responsive. 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 at-risk neonates 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 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 the D-dimer level is high, low molecular-weight heparin therapy 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 to avoid abnormal bleeding during delivery.
See MotherToBaby for further information on medication use during pregnancy.
Therapies Under Investigation
A pilot study on rapamycin therapy for venous malformations has reported beneficial results, especially with regard to pain reduction and improvement in quality of life [Boscolo et al 2015]. A Phase III clinical trial called VASE (vascular anomaly - sirolimus - Europe) has recently completed (EudraCT 2015-001703-32).
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise 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
Sibs of a proband
The risk to the sibs of the
proband depends on the genetic status of the proband's parents.
If the
TEK pathogenic variant found in the
proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental
germline mosaicism.
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) or 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, his or her family members may be at risk.
Prenatal Testing and Preimplantation Genetic Testing
Molecular genetic testing. Once the TEK pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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.
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.
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 Library of Medicine Genetics Home Reference
Vascular Anomaly Patient Association (VASCAPA)
Avenue Hippocrate 75
Brussels B-1200
Belgium
Email: info@vascapa.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
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure. The longest TEK transcript variant NM_000459.4 has 23 exons. For a detailed summary of gene, transcript, and protein information, see Table A, Gene.
Pathogenic variants. Eight pathogenic missense variants have been reported (see ; Table A, HGMD). All pathogenic variants identified to date are located in the parts of the gene coding for the tyrosine kinase domains of the angiopoietin-1 receptor (also known as TIE2). The c.2545C>T substitution was detected in six families [Vikkula et al 1996, Wouters et al 2010, Boon et al 2011].
Table 2.
VMCM-Associated TEK Pathogenic Variants Discussed in This GeneReview
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| DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
| c.2545C>T | p.Arg849Trp |
NM_000459.4
NP_000450.2
|
| c.2690A>C | p.Tyr897Ser |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. The normal angiopoietin-1 receptor (TIE2) is a dimeric receptor tyrosine kinase mostly expressed on vascular endothelial cells. TIE2 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. Pathogenic variants of TEK have a gain of abnormal function that causes ligand-independent increased phosphorylation and can activate STAT1 signaling, in contrast to wild type TEK [Korpelainen et al 1999, Limaye et al 2009, Boon et al 2011]. PI3K-AKT-FOXO1 pathway is activated, leading to reduced PDGF-beta production [Uebelhoer et al 2013]. Loss of the normal allele at the cellular level (i.e., presence of a germline gain-of-abnormal-function pathogenic variant on one allele and an acquired somatic gain-of-abnormal-function pathogenic variant on the other allele) may be the mechanism of disease, as demonstrated by the somatic "second hit" identified in one VMCM tissue [Limaye et al 2009, Soblet et al 2017.
Although all VMCM-associated 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 variation. Uebelhoer et al [2013] and Nätynki et al [2015] document variation by variant type on, for example, phosphorylation, localization, trafficking, and cellular phenotype.
Cancer and Benign Tumors
See Genetically Related Disorders for BRBN, MVM, and unifocal (isolated) venous malformations caused by somatic TEK pathogenic variants. Because these variants are not present in the germline, predisposition to these venous malformations is not heritable.
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Chapter Notes
Revision History
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
