TEK-related venous malformations 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).

The term "TEK-associated venous malformations" is used to describe various clinical entities that are characterized by similar molecular genetic findings (mutations in the TEK gene). The TEK gene encodes a receptor protein (Tie2 receptor), which belongs to the Tie2 protein tyrosine kinase family. The angiopoietin (Ang) Tie signaling system is an endothelial cell-specific ligand-receptor signaling system that is necessary for embryonic cardiovascular and lymphatic development. It also regulates postnatal angiogenesis, vascular remodeling, vascular permeability and inflammation to maintain vascular homeostasis in adult physiology.

The importance of the angiopoietin (Ang)-Tie signaling system and the consistently detectable mutations in various venous malformations in the TEK gene has led to the present classification principle "TEK-associated venous malformations".

TEK-associated venous malformations (VM) comprise a number of different clinical pictures (phenotypes). According to the classification of the International Society for the Study of Vascular Anomalies (ISSVA), the following entities belong to this disease group

• Unifocal/isolated VM
  • Naevus venosus segmentaler (Naevus venosus segmentaler-gene defect not determined) ?
  • Venous malformations unifocal (isolated)
• Multiple cutaneous and mucosal VM (VMCM)
  • Venous malformations multiple cutaneous and mucosal(familial)
  • Venous malformations multiple cutaneous and mucosal (sporadic)
• Blue-Rubber-Bleb nevus (BRBN syndrome)

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). BRBN syndrome is rarely reported, with around 250 cases reported to date (Soblet et al 2017). The low incidence of these phenotypes could be due to their rarity or to misdiagnosis.

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 TEK-induced VM, enlarged vein-like channels with smooth muscle walls of varying thickness are observed. The endothelium is flattened but continuous. If rounded wall cells (glomus cells) are observed, this is a glomuvenous malformation (Brouillard et al 2013)

Clinically related syndromes:

• Bockenheimer syndrome
• Maffucci syndrome
• Glomuvenous malformations (multiple glomangiomas)
• Servelle-Martorell syndrome

All TEK-associated VM, including unifocal VM, MSVM, VMCM and BRBN syndrome, may present with chronic consumptive coagulopathy (CCC) and elevated D-dimer levels (normal: <500 ng/ml). Patients with VM often have elevated D-dimer levels without a concomitant disease that could lead to an increase in D-dimer levels. This increase in D-dimer levels is observed in about 40% of people with isolated VM and in more than 80% of people with VMCM and BRBN syndrome. The elevated D-dimers in conjunction with or without low fibrinogen levels (normal: 150-450 ng/ml) reflect localized intravascular coagulopathy (LIC), which is pathognomonic of VM in the setting of vascular abnormalities.Palpation of phleboliths that develop due to stagnation of blood flow is also pathognomonic of VM. Normal D-dimer levels do not rule out VM, as small VM may have limited intravascular coagulation.

D-dimer levels are also helpful in distinguishing between different types of VM, as more than 95% of individuals with multifocal glomuvenous malformations have normal D-dimer levels (Boon et al 2011). The risk of disseminated intravascular coagulopathy (DIC) caused by an elevated D-dimer level is low unless the affected individual undergoes an intervention, such as surgery or sclerotherapy (see Treatment of manifestations).

Depending on the extent of the findings, sclerotherapy alone or in combination with plastic and reconstructive surgery is indicated, depending on the size and location of the lesions. Low molecular weight heparin (LMWH) should be administered prior to any invasive procedure (sclerotherapy and/or surgery) to avoid disseminated intravascular coagulopathy. If D-dimer levels are elevated and fibrinogen levels are low, low molecular weight heparin should be administered one to two weeks before the procedure, depending on the severity of the coagulation abnormality, and continued for two weeks after the procedure. If fibrinogen levels are normal, treatment with low molecular weight heparin can be initiated the day before surgery. If the lesions are painful and D-dimers are elevated, LMWH can also be used to treat the associated pain.

Sirolimus has recently been used with some success in people with TEK-related VM who do not respond to or are not candidates for surgery or sclerotherapy, and has been shown to reduce pain and functional complications.

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 after trauma or hormonal modulation (e.g. during puberty or pregnancy).

Surveillance: Annual clinical reassessment of TEK-related VM lesions and when symptoms occur. D-dimer levels should be measured every five years when lesions become painful and before any surgical and/or sclerotherapy procedure. Individuals treated with sirolimus should be monitored closely at the beginning and throughout the duration of treatment to adjust dosing and control adverse events.

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. For example, c.2545C>T (p.Arg849Trp) is the most common variant detected in TEK-related (multiple) VMCM, while c.2740C>T (p.Leu914Phe) is the most common variant detected in TEK-related unifocal vascular malformation, but has not been observed in other clinical vascular malformations (Boon et al 2011).

Penetration: About 90 % of individuals with a pathogenic germline variant in TEK (TEK-related VMCM) develop mucocutaneous VM by the age of 20 years; conversely, about 10 % of individuals with a pathogenic germline variant in TEK are not clinically affected (Boon et al 2004, Wouters et al 2010, Soblet et al 2017). The data suggest that pathogenic variants in TEK are sufficient to cause the phenotype. However, individuals have also been found with pathogenic variants in more than one gene (e.g. TEK and PIK3CA).

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