Clinical Guidance

The phenotypic spectrum of individuals with somatic pathogenic variants in TEK is broader than in individuals with germline pathogenic variants in TEK, as somatic mosaicism implies that the percentage, type, and location of cells affected by a pathogenic variant vary between affected individuals. Some TEK pathogenic variants are more likely to be associated with a specific subtype of TEK-related VM. For example, is the most common variant detected in TEK-related VMCM, while is the most common variant detected in TEK-related unifocal VM and has not been observed in VMCM, MSVM, or BRBN syndrome . See the section for information regarding types of genetic variants seen in different types of TEK-related venous malformations.

Source: GeneReviews — "TEK-Related Venous Malformations"

Penetrance

Approximately 90% of individuals who have a germline pathogenic gain-of-function variant in TEK (TEK-related VMCM) develop mucocutaneous VM by age 20 years; conversely, approximately 10% of individuals with a germline pathogenic gain-of-function variant in TEK are clinically unaffected . Reduced penetrance can be explained by the need to acquire a second, somatic pathogenic gain-of-function variant either in the normal allele or the allele with the pathogenic variant, or loss of the normal allele, in the target cell(s) in order to develop a lesion(s) . The penetrance of other TEK-related phenotypes (unifocal VM, MSVM, BRBN syndrome) is currently unknown. It is hard to estimate, as many TEK pathogenic variants may elude detection due to mosaicism.

Source: GeneReviews — "TEK-Related Venous Malformations"

Diagnostic Criteria

TEK-related venous malformations (VM) encompass a range of VM caused by germline (familial or inherited) or somatic (mosaic) pathogenic variants in TEK. Based on the phenotype and type of TEK variant, several phenotypes are delineated .

Suggestive Findings

TEK-related VM should be suspected in a proband with the following clinical features, laboratory findings, and family history.

Clinical Features

Cutaneous and/or mucosal bluish-purple VM can be either single or multiple, and can vary in size from a few millimeters in diameter to larger lesions affecting an entire extremity (see and ).

• Lesions are soft and usually compressible.

• Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.

Source: GeneReviews — "TEK-Related Venous Malformations"

Differential Diagnosis

Table 3. Genes of Interest in the Differential Diagnosis of TEK-Related Venous Malformations

Management Guidelines

No clinical practice guidelines for TEK-related venous malformations (VM) have been published. However, diagnostic and management recommendations have been proposed by the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) (full text). Evaluations Following Initial Diagnosis To establish the extent of disease and management needs in an individual diagnosed with TEK-related VM, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with TEK-Related Venous Malformations

Source: GeneReviews — "TEK-Related Venous Malformations"

Clinical Guidance

Contraceptive pills with high estrogen concentration should be avoided, as VM are estrogen responsive. VM can increase in size and become symptomatic, especially at the initiation of estrogen-based contraception. In some but not all instances stabilization of a VM lesion and diminution of pain may be observed after three months of contraceptive pill use.

Source: GeneReviews — "TEK-Related Venous Malformations"

Therapies Under Investigation

In recent years, multiple trials have reported on the efficacy of MTOR inhibitors in the treatment of slow-flow vascular malformations. A pilot study on rapamycin therapy for venous malformations (VM) reported beneficial results, especially regarding pain reduction and improvement in quality of life . Several Phase II trials showed improvement in symptoms such as pain, bleeding, and functional limitation and improvement in quality of life [, , , , ]. A prospective multicentric Phase III trial (VASE) is currently evaluating the efficacy and safety of sirolimus in slow-flow vascular anomalies that are refractory to standard care (NCT02638389). This study started in January 2016 and has enrolled the intended 250 patients (as of January 2023).

Source: GeneReviews — "TEK-Related Venous Malformations"

Surveillance Guidelines

To monitor existing manifestations of TEK-related VM, the individual's response to treatment, and the emergence of new manifestations, the evaluations in are recommended. Table 7. Recommended Surveillance for Individuals with TEK-Related Venous Malformations

Source: GeneReviews — "TEK-Related Venous Malformations"