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-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 pregnancies at increased risk is possible if the TEK pathogenic variant has been identified in an affected family member.

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 Figure 1):

Figure 1.

Multifocal mucocutaneous venous malformations (marked by arrows) A. On the tongue

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

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:

• With small, multifocal cutaneous and/or mucosal bluish-purple vascular malformations with slow blood flow on Doppler ultrasound; AND/OR
• By identification of a heterozygous gain-of-function pathogenic variant in TEK on molecular genetic testing (see Table 1).

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-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.

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).

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been reported [Wouters et al 2010].

Penetrance

Approximately 90% of individuals who have a germline pathogenic gain-of-function variant in TEK develop mucocutaneous venous malformations by age 20 years; conversely, approximately 10% of individuals with a germline gain-of-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-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].

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:

• MRI of the affected area to evaluate extension into underlying tissue [Dompmartin et al 2010, Boon et al 2011, Boon & Vikkula 2012]
• Measurement of serum D-dimers and fibrinogen level to evaluate for chronic consumptive coagulopathy [Dompmartin et al 2008].
• Consultation with a clinical geneticist and/or genetic counselor

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:

• Every five years;
• If lesions become painful;
• Before any surgical and/or sclerotherapeutic procedure.

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 www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 VMCM have an affected parent.
• The proportion of cases caused by a de novo pathogenic variant is unknown; to date none has been reported.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If neither parent of a proband has clinical evidence of VMCM and the TEK pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. (Though theoretically possible, no instances of germline mosaicism have been reported.)
• The family history of some individuals diagnosed with VMCM may appear to be negative because of a milder phenotypic presentation, incomplete 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 until appropriate evaluations of the proband's parents (i.e., testing for the TEK pathogenic variant identified in the proband and careful dermatologic evaluation) have been performed.
• Note: Somatic mosaicism for TEK pathogenic variants causes either sporadic multifocal venous malformations, isolated venous malformation, or blue rubber bleb nevus syndrome [Limaye et al 2015, Soblet et al 2017]; see Genetically Related Disorders.

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 a TEK pathogenic variant, the risk to the sibs is 50%.
• 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.

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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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 diagnosis 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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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Author Notes

Centre for Vascular Anomalies, Cliniques Universitaires St Luc

Dr Vikkula, de Duve Institute

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