TEK-Related Venous Malformations

Excerpt

Clinical characteristics: TEK-related venous malformations (VM) encompass a range of phenotypes. Following the International Society for the Study of Vascular Anomalies (ISSVA) classification, these include common VM (unifocal/isolated VM or multifocal sporadic VM [MSVM]), multiple cutaneous and mucosal VM (VMCM), and blue rubber bleb nevus (BRBN) syndrome. VM are usually present at birth and grow with time, and new lesions can appear over time in individuals with MSVM, VMCM, and BRBN syndrome. Small lesions are usually asymptomatic; larger lesions can extend into other tissues, including subcutaneous tissues and muscles, causing pain and functional limitations. Malignant transformation has not been reported in TEK-related VM to date.

Diagnosis/testing: The diagnosis of TEK-related VM is established in a proband with suggestive findings and either a heterozygous germline gain-of-function pathogenic variant (VMCM) or a somatic (mosaic) gain-of-function pathogenic variant (unifocal VM, MSVM, BRBN syndrome) identified by molecular genetic testing.

Management: Treatment of manifestations: Sclerotherapy, alone or in combination with plastic and reconstructive surgery, 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-dimers are elevated and fibrinogen levels are low, LMWH should be initiated one to two weeks before surgery, depending on severity of coagulation abnormality, and continued for two weeks after surgery. If fibrinogen levels are normal, LMWH can be initiated the day before surgery. If lesions are painful and D-dimers are elevated, LMWH can also be used to treat the associated pain. For gastrointestinal VM, endoscopic evaluations with abdominal imaging are needed. Sirolimus has been recently used with some success in individuals with TEK-related VM who do not respond to or are ineligible for surgery or sclerotherapy, and has been shown to reduce pain and functional complications.

Surveillance: Clinical reevaluation of TEK-related VM lesions annually and if symptoms arise. D-dimer levels should be measured every five years, if lesions become painful, and before any surgical and/or sclerotherapeutic procedure. Individuals on sirolimus should be closely followed at the beginning and throughout the course of their treatment, in order to modify the dosage as well as manage adverse events.

Agents/circumstances to avoid: Contraceptive pills with high estrogen concentration.

Evaluation of relatives at risk: Physical examination of at-risk neonates to identify those who can benefit from early treatment.

Pregnancy management: D-dimer levels should be evaluated every one to three months during pregnancy (depending on the symptoms) and prior to delivery to adjust LMWH therapy and to avoid abnormal bleeding during delivery.

Genetic counseling: TEK-related VM are either inherited in an autosomal dominant fashion (TEK-related VMCM) or caused by somatic (mosaic) variants (TEK-related unifocal VM, MSVM, and BRBN syndrome).

For TEK-related VMCM, most individuals have an affected parent. The proportion of cases caused by a de novo pathogenic variant is unknown; none have been reported to date. In some affected individuals, lesions are small. Therefore, careful skin examination is needed in order to determine if a family member is affected. Each child of an individual with TEK-related VMCM has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the TEK pathogenic variant has been identified in an affected family member.

With regards to other TEK-related phenotypes, unifocal VM, MSVM, and BRBN syndrome are not known to be inherited, as identified pathogenic variants to date are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date. The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in TEK would be expected to be the same as in the general population. Due to mosaicism, the risk for transmission to offspring is expected to be less than 50%.