Table 9.

Syndromes associated with vascular anomalies.

Syndrome	Clinical phenotype	Candidate gene	Protein function or suspected role (if known)	Clinical work-up	References
CLOVES syndrome	• Characterized by congenital lipomatous overgrowth • Vascular malformations • Epidermal nevi • Skeletal anomalies	PIK3CA, due to mosaic or missense mutations	• Catalytic alpha subunit of PI3K. Somatic activating mutation that increases PI3K/AKT/mTOR signaling	• Brain MRI • X-rays for leg length discrepancy • Scoliosis screen • Echocardiogram • EEG • Renal US to rule out anomalies and q3-6 months to screen for Wilms tumor • Screening for paraspinal high-flow lesions with spinal cord ischemia • Thrombophilia evaluation • Developmental • Feeding assessment	(3, 15)
Klippel-Trenaunay syndrome	• Characterized by slow-flow capillary-lymphatic-venous malformations and soft tissue overgrowth of an extremity and/or trunk • Often involves the pelvis as well. Can be unilateral or bilateral	PIK3CA, some cases AGGF1	• Catalytic alpha subunit of PI3K. Somatic activating mutation that increases PI3K/AKT/mTOR signaling • Angiogenic factor with G patch and FHA domains, increases angiogenesis in vitro	• MRI imaging of affected area • Thrombophilia evaluation and labs for localized intravascular coagulation	(3, 15)
Megalencephaly-capillary malformation syndrome (MCAP)	• Congenital megalencephaly or hemimegalencephaly • Reticulate capillary stains • CM of the lip/philtrum • Asymmetry, focal, or generalized overgrowth • Hypotonia • Seizures • Mild to severe intellectual disability • Syndactyly	PIK3CA, from brain tissue	• Catalytic alpha subunit of PI3K. Somatic activating mutation that increases PI3K/AKT/mTOR signaling	• Brain MRI q 6 months for the first 2 years then yearly till 8 years to rule out neurological complications • X-rays for leg length discrepancy • Scoliosis screen • EEG • Echocardiogram • Renal US to rule out anomalies and q 3 months to screen for Wilms tumor • Developmental and feeding assessment • Sleep evaluation • Thrombophilia evaluation	(3, 10, 15)
Maffucci syndrome	• Multiple spindle cell hemangiomas associated with multiple enchondromas • Vascular lesions often do not appear until puberty • Patients have increased risk for malignancy	IDH1 and IDH2	• Mutant enzymes catalyze the reduction of alfa-ketoglutarate to D-2-hydroxyglutarate, cause downstream genomic hypermethylation	• Screening of lesions due to malignancy potential • Risk of many types of malignancy reported (chondrosarcomas, gliomas, ovarian tumors, and other sarcomas) • Limb length x-rays and imaging of the extremities for other malformations	(3, 10, 60)
Proteus syndrome	• Bony and soft tissue overgrowth that develops and progresses rapidly in the toddler period and tends to plateau after adolescence • Increased risk of malignancy • Pulmonary complications • Increased risk thrombus	AKT1	• Intracellular PI3K/AKT/mTOR signaling/apoptosis	• Scoliosis screen • Skin exam • Thrombophilia evaluation and monitoring for DVT and PE • Developmental assessment • Monitoring for bullous pulmonary disease	(3, 10, 11)
Parkes weber syndrome	• Similar to CM-AVM but with overgrowth of affected limb	RASA1, loss of function mutation	• Intracellular signaling, RasGTPase	• Brain/spine MRI • US shows fast-flow lesion	(3, 9, 11, 15)
Familial intraosseous vascular malformation	• Extensive vascular lesions in the intraosseus spaces of the craniofacial bones associated with other midline defects • AR inheritance • Intraosseous hemangioma often in the vertebral column or the skull • Most commonly affected bones are the mandible and the maxilla • Life threatening progressive expansion of the jaw • Craniofacial and other intramembranous bones caused by malformed blood vessels	ELMO2	• Translation of extracellular signals to cellular movements	• MRI head and neck • Midline screen to look for diastasis recti, supraumbilical raphe and hiatal hernia	(3, 61)