TEK gene

Multiple cutaneous and mucosal venous malformations

Genetic changes that cause disease or increase the risk of disease are called pathogenic variants. Pathogenic variants in the TEK gene can predispose individuals to develop multiple cutaneous and mucosal venous malformations (also known as VMCM). People with VMCM develop bluish patches (lesions) on the skin (cutaneous) and the moist tissues that line body cavities (mucous membranes). These lesions represent areas where the underlying venous blood vessels developed abnormally (venous malformations).

The pathogenic variants in the TEK gene that are associated with VMCM typically change single protein building blocks (amino acids) in the TEK receptor. The most common pathogenic variant replaces the amino acid arginine with the amino acid tryptophan at position 849 (written as Arg849Trp or R849W). This variant is called a "gain-of-function variant" because it causes the TEK receptor to become overactive, which leads to excessive signaling. This impairs the communication between endothelial cells and smooth muscle cells, disrupting the pattern of growth for endothelial cells. As a result, venous blood vessels develop abnormally, leading to the venous malformations seen in people with VMCM.

VMCM is inherited in an autosomal dominant pattern, which means that one altered copy of the TEK gene is sufficient to predispose individuals to develop venous malformations. However, evidence suggests that the inherited TEK variant alone may not always be enough to cause a particular venous malformation to develop. An additional pathogenic variant may arise during a person's lifetime and be present only in certain cells. This type of variant is called a somatic variant, and it may help explain why venous malformations develop in different areas of the body and why their number and location vary among affected individuals.

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Somatic pathogenic variants in the TEK gene have been associated with Bockenheimer disease, a condition that is characterized by extensive venous malformations that worsen over time and typically affect one arm or leg. Individuals may experience pain, swelling, fractures, and limited mobility in the affected arm or leg. The condition is often caused by the substitution of one amino acid for another in the TEK receptor. This results in excessive TEK receptor signaling, which leads to the abnormal development of venous blood vessels.  

Somatic pathogenic variants in the TEK gene can cause blue rubber bleb nevus (BRBN) syndrome. Affected individuals are typically born with a large lesion, which is often the first sign of the condition. As people with BRBN syndrome age, additional lesions appear. Cutaneous lesions on the palms of the hands and the soles of the feet are common. Many people with BRBN syndrome have lesions in the small intestine, which can cause internal bleeding; iron deficiency; and other complications, such as the twisting of a loop of intestines around itself (volvulus). Blood clotting issues are common in people with BRBN syndrome. Affected individuals typically have two somatic, gain-of-function variants in the TEK gene, leading to excessive TEK receptor signaling and the development of venous malformations. Because this condition is caused by somatic variants, BRBN syndrome is not inherited.

Somatic pathogenic variants in the TEK gene can also cause multifocal sporadic venous malformations (MSVM). This condition is characterized by small lesions that often affect the mouth (oral mucosa) and the skin on the arms, legs, face, and neck. However, some people with the TEK gene variants that cause MSVM do not have the signs and symptoms that are associated with the condition (asymptomatic). People with MSVM typically have two somatic, gain-of-function variants in the TEK gene, leading to the development of venous malformations. Because the condition is caused by somatic variants, MSVM is not inherited. 

Somatic pathogenic variants in the TEK gene can also cause unifocal venous malformation (also called unifocal VM or isolated VM). People with unifocal VM have a single lesion. Although the size and location of the lesion can vary, unifocal VMs are typically located on the arms, legs, face, neck, or trunk. Affected individuals may experience pain, especially if the lesion extends into the joint or muscle. If the unifocal VM affects the airway, it can be life-threatening. Approximately 60 percent of unifocal VMs are caused by a somatic, gain-of-function variant in the TEK gene. The most common pathogenic variant replaces the amino acid leucine with phenylalanine at position 914 (written as Leu914Phe), resulting in the production of an altered TEK receptor. This causes excessive signaling and abnormal venous blood vessel development. Because the condition is caused by a somatic variant, unifocal VM is not inherited.

Researchers are working to understand how pathogenic variants in the TEK gene can cause a variety of similar but distinct conditions.