Table 5.

Somatic disorders involving lymphatic malformations.

Associated malformation or syndrome	Clinical phenotype	Candidate gene	Protein function or suspected role (if known)	Clinical work-up	References
Sporadic LMs	• Localized or extensive malformed lymphatic vessels in the skin or deep soft tissues • Predilection for head/neck areas	PIK3CA	• Catalytic alpha subunit of PI3K. Somatic activating mutation that increases PI3K/AKT/mTOR signaling	• Imaging of involved site with MRI • Evaluation for other sites of disease if clinically indicated	(3, 10–12)
Generalized lymphatic anomaly (GLA)	• Previously known as lymphangiomatosis • Diffuse or multifocal LMs throughout the skin, soft tissues, abdominal, and thoracic viscera • Pericardial and pleural effusions may be noted • May have significant bone involvement	PIK3CA	• Catalytic alpha subunit of PI3K. Somatic activating mutation that increases PI3K/AKT/mTOR signaling	• Full body imaging with CT and/or MRI • Screening for coagulopathy (PT, PTT, fibrinogen, d-dimer) • Biopsy not necessary • Echo	(10, 11, 42)
Gorham stout syndrome, aka “disappearing bone disease”	• Progressive osteolysis with replacement of bone by soft tissue and vascular channels, primarily lymphatic in origin • Defining characteristic is disappearance of bone rather than a mass lesion in bone	Unknown	• Likely involvement of PI3K/AKT/mTOR signaling pathway	• Full body imaging with CT and/or MRI • Screening for coagulopathy (PT, PTT, fibrinogen, d-dimer) • Biopsy not necessary • Echo	(3, 42, 43)
Kaposiform lymphangiomatosis (KLA)	• Systemic and frequently aggressive lymphatic anomaly • More extensive thoracic involvement than GLA • Frequently associated with coagulopathy, effusions, and intralesional hemorrhage • Systemic involvement is common	NRAS, possible	• Intracellular RAS signaling. A proto-oncogene that encodes a small GTPase that regulates cell proliferation in the RAS/MAPK and PI3K/AKT/mTOR signaling pathways	• Full body imaging with CT and/or MRI • Consider echocardiography • Screening for coagulopathy (PT, PTT, fibrinogen, d-dimer) • Consider angiopoietin and VEGFR3 screening • Biopsy not necessary	(3, 10, 11, 44, 45)
Congenital pulmonary LM	• LMs in the lungs, heart, pancreas, kidneys, and mesentery • Respiratory distress at birth due to pulmonary hypoplasia secondary to chylous pleural effusions • May overlap with Noonan, Turner, and Down syndromes	CCBE1	• Extracellular guidance molecule for migrating lymphatic endothelial cells, enhances lymphangiogenic activity of VEGF-C	• Full body imaging with CT and/or MRI • Consider echocardiography • Developmental and neurologic screening	(3, 15)