Table 4.

Inherited/germline conditions involving venous malformations.

Associated malformation or syndrome	Clinical phenotype	Candidate gene/inheritance	Protein function or suspected role (if known)	Clinical evaluation	References
PTEN-associated venous anomalies	• Hamartoma of soft tissue, intramuscular vascular lesions, with fast-flow lesions in 86% • Increased risk of cancer	PTEN AD	• Tumor suppressor	• Head circumference • Skin exam • Brain MRI with contrast • Cancer screening (thyroid, breast, uterine, colon)	(3, 32–34)
Mucocutaneous venous malformations (VMCM)	• Small, multifocal bluish muco-cutaneous lesions	TIE2/TEK AD	• Endothelial cell-specific tyrosine kinase receptor. Important for angiogenesis (angiopoietin receptor)	• Physical exam, consider imaging • Consider cardiac work up	(3, 15, 35)
Cerebral cavernous malformation, familial	• Cerebral lesions dilated channels with endothelial cell layers that have defective tight junctions in the brain, retina and spinal cord • Majority present in between the second and fifth decades with seizures, focal neurologic findings, headaches, and cerebral hemorrhage • Cutaneous vascular lesions in 9% and retinal vascular lesions in 5%	KRIT1 CCM2 PDCD10 AD	• Loss-of-function mutations affecting subendothelial matrix, vascular structure, and adhesion	• Brain MRI with gradient echo or susceptibility weighted imaging	(3, 36)
Glomuvenous malformations or Glomangiomas	• Superficial, multiple raised or plaque-like lesions • Cobblestone appearance, painful on palpatio	GLMN AD, 100% penetrance with variable expressivity	• Phosphorylated protein that is a member of the Skp1-Cullin-F-box-like complex • Essential for normal development of the vasculature • Loss of function mutation, likely requires a somatic second hit	• Detailed skin exam • Genetic testing and counseling • Biopsy vs. removal if concern about diagnosis • No routine imaging unless clinical concern	(3, 15, 26, 37)
Hyperkeratotic cutaneous capillary-venous malformation (HCCVM)	• Crimson-colored irregularly shaped lesions that extend into the dermis and hypodermis • Composed of dilated capillaries and blood-filled venous-like channels • Associated with cerebral capillary malformations, which may present with headaches, seizures, and intracranial hemorrhag	KRIT1 (also known as CCM1) CCM2 CCM3 Possible AD	• RAS antagonist, may be involved in cellular adhesion and vascular integrity. The CCM proteins interact together and dysfunction of the CCM signaling complex leads to altered vascular integrity and endothelial cell organization	• Detailed skin exam • Brain imaging for cerebral capillary malformations	(38, 39)
Varicose veins	• Twice as common in females as males	FOXC2 AD, with reduced penetrance	• Unkown	• Physical exam with referral to vascular surgeon if symptomatic concerns	(3, 40)