Venous Malformations, Multiple Cutaneous And Mucosal

A number sign (#) is used with this entry because of evidence that multiple cutaneous and mucosal venous malformations can be caused by heterozygous mutation in the TEK (TIE2) gene (600221), which encodes the epithelial-specific tyrosine kinase receptor, on chromosome 9p21.

Description

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.

Clinical Features

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.

Mapping

Boon et al. (1994) demonstrated that the disorder did not map to 9q, the site of the mutation in hereditary hemorrhagic telangiectasia type 1 (HHT1; 187300). On the other hand, they were able to demonstrate that the locus for multiple cutaneous and mucosal venous malformations in this family lies within a 24-cM interval on 9p, defined by the markers D9S157 and D9S163. Gallione et al. (1995) confirmed linkage to 9p in a second family.

Heterogeneity

Calvert et al. (1999) excluded linkage to 9p21 in at least 1 VMCM family, thus providing evidence that this disorder displays genetic heterogeneity.

Molecular Genetics

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.

Other Features

DNA pooling is a powerful and efficient method for rapid genomewide linkage scans in autosomal recessive diseases in inbred populations, where affected individuals are likely to be homozygous for alleles at loci surrounding the disease gene. This strategy exploits the fact that affected individuals in inbred families share a chromosomal region inherited from a common ancestor surrounding the disease locus. Traditionally, genotype results are generated for individual DNA samples using a given marker or markers. In the DNA pooling strategy, DNA from multiple affected and unaffected individuals from each family, as well as population controls, are pooled in separate lanes and simultaneously amplified by PCR with a given marker. Markers linked to and in association with the disease gene will show loss of heterozygosity and hence a different pattern of alleles from appropriate control groups. Unlinked markers should demonstrate an allele distribution that is similar to control lanes. Damji et al. (1998) investigated whether this approach would detect linkage in autosomal dominant disorders, as suggested by Kanis et al. (1995), where affected individuals within a given family may share 1 allele identical by descent at loci tightly linked to the disease. They used 2 outbred pedigrees in which familial venous malformations and hereditary hemorrhagic telangiectasia type 1 are linked to sites at opposite ends of chromosome 9. These were the kindreds reported by Gallione et al. (1995) and McDonald et al. (1994), respectively. Separate pools of DNA from 21 family members affected with VMCM and 17 with HHT1, 9 unaffected family members, and 25 unrelated population controls were established. In both autosomal dominant diseases investigated, quantitative DNA pooling detected shifts in allele frequency, thus identifying areas of known linkage. Although the false-positive rate appeared to be high, the approach was thought still to serve the purpose of reducing the amount of genotyping required.