Cutaneomucosal venous malformation (VMCM) is an uncommon, heritable form of venous malformation in which lesions tend to be multifocal and small. They are comprised of grossly dilated vascular spaces lined by a single continuous layer of endothelial cells, ... Cutaneomucosal venous malformation (VMCM) is an uncommon, heritable form of venous malformation in which lesions tend to be multifocal and small. They are comprised of grossly dilated vascular spaces lined by a single continuous layer of endothelial cells, with areas of relative lack of surrounding mural cells, suggesting a defect in their recruitment. Some VMCM patients have venous malformations located in internal organs, and some have additional anomalies, including cardiac malformations (summary by Wouters et al., 2010). Another form of autosomal dominant venous malformation, blue rubber bleb nevus (112200), is of uncertain relationship to VMCM. Multiple cerebrovenous anomalies without cutaneous lesions are also familial; see cerebral cavernous malformations (116860). Glomuvenous malformations (138000) are similar to but clinically distinguishable from VMCMs.
Pasyk et al. (1984) described a family in which multiple vascular malformations, including cavernous hemangiomas, arteriovenous malformations, and capillary hemangiomas, occurred in 25 persons over 5 generations in an autosomal dominant pattern. Slightly reduced penetrance was suggested by ... Pasyk et al. (1984) described a family in which multiple vascular malformations, including cavernous hemangiomas, arteriovenous malformations, and capillary hemangiomas, occurred in 25 persons over 5 generations in an autosomal dominant pattern. Slightly reduced penetrance was suggested by the fact that a clinically unaffected woman had a child with a hemangioma on the foot and that in the part of the pedigree with the most complete documentation, the ratio of affected to unaffected was 15:20. Histopathologic examination in most cases revealed typical cavernous hemangiomas, composed of large, lacunar vascular spaces forming compact masses. The walls of these dilated vessels were relatively thin, lined with a single layer of endothelium; no smooth muscle or elastic tissue surrounded the vessels. Pasyk et al. (1984) noted that none of the patients in this family had a history of any symptoms that would suggest intracranial involvement: there had been no seizure disorders in any of the generations, nor had there been a death from intracranial catastrophe. In 15 members of 3 generations of a kindred and by implication in a sixteenth member in an earlier generation, in a pedigree pattern consistent with autosomal dominant inheritance, Boon et al. (1994) described cutaneous and mucosal venous malformations. They pictured an 18-year-old male with a 'slow-flow' venous malformation in the tongue which bled intermittently and caused deformation of the maxilla and mandible. They also pictured characteristic small cutaneous venous malformations located on the posterior aspect of the ear in 1 member. The lesions varied in size from 0.5 to 2 cm, except for the lesion on the tongue which measured 5 cm. Lesions were located on the arms and legs, face, oral mucosa, or genitalia. Some were present at birth; most lesions appeared by puberty. None of the family members had a history of gastrointestinal bleeding and occult blood was not demonstrated by guaiac testing of the stool. Gallione et al. (1995) restudied the large family with multiple vascular malformations originally described by Pasyk et al. (1984), noting that of 337 members over 7 generations, 56 individuals were affected. The location of the venous malformations was almost identical for several family members. In most cases, the lesions were small, enlarged with time, and were asymptomatic. A few of the females observed an increase in size of the vascular lesions approximately 1 week before menstruation and a subsequent decrease in size during menstruation. The lesions were present on the face and mucous membranes, including the lips, tongue, cheeks, tonsils, and larynx. Some members had venous malformations within internal organs. One developed 2 vascular tumors in the large intestine and required blood transfusions because of excessive bleeding. Two members of the family died from complications of these vascular abnormalities. Pathologic examination in one of these patients showed vascular tumors within the stomach, liver, pancreas, and spleen. Gallione et al. (1995) noted that the disorder in this family was similar to the blue rubber bleb nevus syndrome (112200), pointing out that the family originally described by Bean (1958), like their family, had gastrointestinal bleeding from vascular lesions. Gallione et al. (1995) suggested that blue rubber bleb nevus syndrome might be a subset in the general category of familial venous malformations. Wouters et al. (2010) studied 26 affected individuals from 12 unrelated families with VMCM. Cutaneous lesions were mostly located in the cervicofacial region (18 of 26) and/or limbs (21 of 26), and less often on the trunk (9 of 26). Lesions on the lips, tongue, and buccal mucosa were frequent (15 of 26). The venous malformations were generally small (less than 5 cm), and over 80% of patients had more than 2 lesions. Some individuals had venous malformations located in internal organs, including pulmonary, gastrointestinal, renal, and brain lesions. Localized intravascular coagulopathy was documented by elevated D-dimers in 5 of 13 patients tested, and appeared to be associated with overall lesion volume. Some patients had additional anomalies, including restrictive perimembranous ventricular septal defect, which was present in a mother and 2 daughters as well as a woman from an unrelated family.
The endothelial cell-specific receptor tyrosine kinase TIE2 (TEK; 600221) had been mapped to 9p21. To test whether TIE2 is localized to the interval where the VMCM1 locus is situated, Vikkula et al. (1996) used 2 human melanoma cell ... The endothelial cell-specific receptor tyrosine kinase TIE2 (TEK; 600221) had been mapped to 9p21. To test whether TIE2 is localized to the interval where the VMCM1 locus is situated, Vikkula et al. (1996) used 2 human melanoma cell lines containing previously defined homozygous deletions of 9p and a YAC contig covering the 8-cM region from the IFN gene cluster to the marker D9S161. They showed that indeed the TIE2 gene lies within the linked interval. They then analyzed TIE2 as a candidate gene in the 2 large VMCM pedigrees previously linked to 9p by Boon et al. (1994) and Gallione et al. (1995), and identified a 2545C-T transition in the TIE2 gene, predicted to result in an arg489-to-trp amino acid change (R849W; 600221.0001). Calvert et al. (1999) found the R849W mutation in an unrelated VMCM family, and identified heterozygosity for a different missense mutation within the same domain of TIE2 in another kindred (Y897S; 600221.0002). Cell transfection experiments using constructs containing either the R849W or the Y897S mutation demonstrated that the receptors containing either mutation showed ligand-independent hyperphosphorylation, suggesting a gain-of-function mechanism for development of venous malformations in these families. Wouters et al. (2010) analyzed the TEK gene in 26 affected members of 12 families with VMCM, and identified heterozygosity for the R849W mutation in 14 patients from 6 of the families. In the remaining families, 6 different heterozygous missense mutations were identified, respectively (see, e.g., 600221.0003 and 600221.0004). All of the VMCM-associated mutations resulted in ligand-independent hyperphosphorylation of TEK2; although the levels of hyperphosphorylation were highly variable, Wouters et al. (2010) observed no genotype-phenotype correlation. - Sporadic Venous Malformations Limaye et al. (2009) assessed whether localized tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common than mucocutaneous venous malformations. Limaye et al. (2009) identified 8 somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations. The somatic mutations included one causing a frequent L914F substitution (leu914 to phe) and several double mutations in cis, all of which resulted in ligand-independent TIE2 hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wildtype TIE2 and the common, inherited R849W (600221.0001) mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in 2 individuals suggested a common origin for the abnormal endothelial cells at the distant sites. Limaye et al. (2009) concluded that their data showed that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms and pinpointed TIE2 pathways as potential therapeutic targets for venous malformations.
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. ...
DiagnosisClinical 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. FigureFigure 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. TestingD-dimer concentration may be elevated in individuals with multifocal VMCM, whereas it is normal in individuals with multifocal glomuvenous malformations. Normal: <500 ng/mLIn VMCM: normal to 6900 ng/mL [Dompmartin et al 2008, Dompmartin et al 2010, Wouters et al 2010, Boon et al 2011]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 MalformationsView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTEKSequence analysisSequence variants 2100%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.
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. ...
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).
No genotype-phenotype correlation has been reported. ...
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.
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.” ...
Differential DiagnosisGlomuvenous 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
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:...
ManagementEvaluations 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:In an individual diagnosed with multiple cutaneous and mucosal venous malformations (VMCM), MRI to evaluate extension into underlying tissue [Dompmartin et al 2010, Boon et al 2011, Boon & Vikkula 2012]Medical genetics consultationTreatment of ManifestationsManagement 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 ComplicationsIf 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). SurveillanceBecause 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 AvoidContraceptive 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 RiskEvaluating 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 InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTEK9p21.2Angiopoietin-1 receptorTEK homepage - Mendelian genesTEKData 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) View in own window 600195VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL; VMCM 600221TEK TYROSINE KINASE, ENDOTHELIAL; TEKNormal 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 GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.2545C>Tp.Arg849TrpNM_000459.3 NP_000450.2c.2690A>Cp.Tyr897SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 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].