Table 3.
Somatic disorders involving venous malformations.
| Associated malformation or syndrome | Clinical phenotype | Candidate gene | Protein function or suspected role (if known) | Clinical evaluation | References |
|---|---|---|---|---|---|
| Sporadic VMs | • Solitary, localized, and non-familial • Soft, mass or sponge-like lesion with blue or purple coloration |
TIE2/TEK
PIK3CA |
• Endothelial cell-specific tyrosine kinase receptor. Important for angiogenesis (angiopoietin receptor). Gain of function mutations, probably affects endothelial cell behavior, may involve paracrine signaling between endothelial and smooth muscle cells, down-regulation of PDGF-beta production, only mucocutaneous veins are affected • Catalytic alpha subunit of PI3K. Somatic activating mutation that increases PI3K/AKT/mTOR signaling |
• US or MRI of lesion depending on location and symptoms • Screening for localized intravascular coagulopathy (PT, PTT, fibrinogen, d-dimer) • Consider brain MRI |
(3, 10–12, 15) |
| Multifocal VM | • Rare, multifocal variant • Tend to be mosaic for first mutation with 2nd hit |
TIE2/TEK | • Endothelial cell-specific tyrosine kinase receptor. Important for angiogenesis (angiopoietin receptor) | • Consider whole body MRI | (11, 12) |
| Verrucous VM | • Raised reddish-purple hyperkeratotic lesion (extremities) • Enlarge over time, more hyperkeratotic with increased bleeding |
MAP3K3 | • Somatic activating mutation that may increase RAS/MAPK signaling | • Skin exam • Consider evaluation for underlying bleeding diathesis |
(3, 10, 12, 29) |
| Fibroadipose vascular anomaly (FAVA) | • Within a muscle; increased fibroadipose tissue and smaller, non-spongiform vessels • Often single limb, appears slightly enlarged |
PIK3CA | • Catalytic alpha subunit of PI3K. Somatic activating mutation that increases PI3K/AKT/mTOR signaling | MRI or US of the lesion | (3, 10, 12) |
| Blue rubber bleb nevus syndrome | • Sporadic, some AD inheritance • Multiple cutaneous and internal VM • Intestinal and hepatic • Tens to hundreds of blue or purple, compressible, and hyperkeratotic |
TEK/TIE2 | • Endothelial cell-specific tyrosine kinase receptor. Important for angiogenesis (angiopoietin receptor) | • MRI or ultrasound, consider full body MRI consider biopsy • Screening for localized intravascular coagulopathy (D-dimer, fibrinogen, PT, PTT) • Urinalysis for hematuria • Screening for iron deficiency anemia • Endoscopy/colonoscopy |
(3, 10–12, 15, 30, 31) |
| Cerebral cavernous malformation (CCM) | • Immature vessels reflecting abnormal angiogenesis presents with seizures, headaches, hemorrhage, and neurologic defects |
KRIT1 (CCM1)
CCM2 CCM3 Sporadic or AD |
• Adaptor protein Integrin β1 pathway involved in arterial specification, cell adhesion, endothelial cell junctions, and migration • Adaptor protein, scaffold protein, overlaps with KRIT1 • Apoptosis, VEGF signaling. Overlaps with KRIT1 • The CCM proteins interact together and dysfunction of the CCM signaling complex leads to altered vascular integrity and endothelial cell organization. They suppress RhoA GTPase signaling |
• Brain MRI with gradient echo or susceptibility weighted imaging | (3, 9–12, 15) |