Unifocal (isolated) venous malformation Q27.9

The title TEK-associated venous malformations (VM) is based on the dual naming system proposed by Biesecker et al. (2021) for the differentiation of genetic disorders. Therefore, this term encompasses all previously known TEK-associated VM phenotypes, including multiple cutaneous and mucosal VM (VMCM), multifocal sporadic VM (MSVM), unifocal (isolated) VM and blue-rubber bleb nevus (BRBN) syndrome.

History: Terms previously used to describe VM include "cavernous angioma", "cavernous hemangioma" and "veinctasia". The term "mucocutaneous venous malformation" was coined in 1994 for the vascular lesions identified in a large multigenerational family from the United States in which the TEK locus was first identified (Boon et al. 1994).

Venous malformations (VM) are often regarded as the most common subtype of vascular malformations. They occur in maternity hospitals with an incidence of between 1:2,000 and 1:5,000 live births. More than 90 % of VM occur sporadically and in isolation (Wassef et al. 2015). Although the prevalence of TEK-related VM such as MSVM, VMCM and BRBN syndrome is not known, it is far lower than that of sporadic unifocal VM. VMCM is estimated to account for less than 1% of individuals with venous anomalies treated in multidisciplinary centers specializing in vascular anomalies (Boon et al 2004).

Genotype-phenotype correlations: The phenotypic spectrum of individuals with somatic pathogenic TEK variants is broader than that of individuals with pathogenic TEK germline variants. As a result of somatic mosaicism, the percentage, type and location of cells affected by a pathogenic variant may vary considerably between affected individuals. Some pathogenic TEK variants may be associated with a particular subtype of TEK-associated VM. C.2740C>T (p.Leu914Phe)is the most common variant detected in TEK-related unifocal vascular malformation. It has not been observed in other clinical vascular malformations (Boon et al 2011).

About 40% of VM occurs in the extremities, 40% in the cervicofacial region and 20% in the trunk.

TEK-related venous malformations (VM) are slow-flowing venous lesions that appear as a light to dark skin discoloration over a soft, compressible mass and develop mainly in skin, subcutaneous or mucosal tissue.

In principle, venous malformations (VM) can affect any tissue or organ, including the skin, muscles, joints, intestines and central nervous system. They are usually present at birth.

Venous malformations grow and expand slowly over time (Dompmartin et al 2010). Palpation may reveal phleboliths that had developed due to long-standing local thrombosis. A rapid increase in the size of the lesions can be observed following trauma or hormonal modulation (e.g. during puberty or pregnancy).

The clinical picture is therefore variable and depends on the size, location and mass effect on neighboring organs. The most common complications of unifocal VM include aesthetic deformities and chronic pain due to joint, tendon or muscle involvement.

Depending on the organ or area affected, functional limitations range from muscle weakness and limb length discrepancy to difficulty eating, speaking, breathing and physical deformities. Other symptoms include bleeding and, in the case of combined venolymphatic malformations, recurrent infections and oozing. In some cases, VM can be life-threatening due to the expansion or obstruction of vital structures such as the airways.

1. Ada F et al. (2018) Surgical treatment of Servelle-Martorell syndrome. Turk Gogus Kalp Damar Cerrahisi Derg 26:301-304.
2. Ali B et al. (2020) Diffuse venous malformations of the upper extremity (Bockenheimer disease): diagnosis and management. Plast Reconstr Surg 146:1317-1324.
3. Ballieux F et al (2015) Blue bleb rubber nevus syndrome. Handb Clin Neurol 132:223-230.
4. Beluffi G et al. (2004) Jejunal intussusception in a 10-year-old boy with blue rubber bleb nevus syndrome. Pediatr Radiol 34:742-745.
5. Bhatnagar A et al. (2012) A rare case of servelle martorelle syndrome-extensive angioosteohypotrophic lesion of upper limb. World J Surg Res 1:6-11.
6. Biesecker LG et al. (2021) A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet 108:8-15.
7. Blei F et al. (1998) Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 134:718-722.
8. Boon LM et al. (1994) Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet 3:1583-1587.
9. Boon LM et al. (2011) Pathogenesis of vascular anomalies. Clin Plast Surg. 2011a;38:7-19.
10. Boon LM et al. (2013) Molecular genetics of vascular malformations. In: Mulliken JB, Burrown PE, Fishman SJ, eds. Mulliken and Young's Vascular Anomalies: Hemangiomas and Malformations. 2 ed. New York, NY: Oxford University Press: 327-375.
11. Boon LM et al.(2011) Vascular malformations. In: Irvine A, Hoeger P, Yan A, eds. Harper's Textbook of Pediatric Dermatology. 3 ed. Wiley-Blackwell:112.1-112.24.
12. 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]
13. Brouillard P et al. (2013) Genotypes and phenotypes of 162 families with a glomulin mutation. Mol Syndromol 4:157-164.
14. Kubiena HF et al. (2006) Genuine diffuse phlebectasia of Bockenheimer: dissection of an eponym. Pediatr Dermatol 23:294-297.
15. Nahm WK et al. (2004) Venous malformations in blue rubber bleb nevus syndrome: variable onset of presentation. J Am Acad Dermatol 50(5 Suppl):101-106.
16. Pasyk KA et al. (1984) Familial vascular malformations. Report of 25 members of one family. Clin Genet 26:221-227.
17. Seront E et al. (2018) Venous Malformations of the Head and Neck. Otolaryngol Clin North Am 51:173-184.
18. Seront E et al (2024) TEK-Related Venous Malformations. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301733.
19. Soblet J et al. (2013) Variable somatic TIE2 mutations in half of sporadic venous malformations. Mol Syndromol 4:179e83.
20. Soblet J et al. (2017) Blue rubber bleb nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations. J Invest Dermatol 137:207-216.
21. Wouters V et al. (2008) TIE2 and cutaneomucosal venous malformation. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. New York, NY: Oxford University Press.
22. Wouters V et al. (2010) Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur J Hum Genet 18:414-420.
23. Zhou J et al. (2021) Efficacy and safety of sirolimus for blue rubber bleb nevus syndrome: a prospective study. Am J Gastroenterol 116:1044-1052.