References

2026

Brown G, McNab S, Keogh S, Massie J, Eastaugh L, Pathmanathan L, et al. Resolution of Refractory Chylous Effusions With Targeted MEK Inhibition in NRAS Q61R-Driven Kaposiform Lymphangiomatosis: A Case Report. Case Rep Pediatr 2026;2026:7037459.

PMID 42639465 PMC13501887 doi:10.1155/crpe/7037459 1 report · KLA

NRAS Q61R
Henslee SB, Wooderchak-Donahue WL, Grimmer JF, Szankasi P, Bolia A, Frigerio A, et al. Molecular Characterization of Vascular Anomalies Tissues Guides Clinical Diagnosis. Lymphat Res Biol 2026:15578585251391569.

PMID 41574430 doi:10.1177/15578585251391569 2 reports · LM

PIK3CA *1069Pheext*4 PIK3R1 E462_R465del
Yang G, Ren H, Wang J, Chen W, Li X, Chen S, et al. NRAS mutation in a central conducting lymphatic anomaly and PPFIBP1::ROS1 fusion in a Gorham-stout disease patient. Hum Mol Genet 2026;35:ddag070.

PMID 42544506 doi:10.1093/hmg/ddag070 1 report · CCLA

NRAS Q61R

Fox MD, Kumar S, Britt AD, Srinivasan AS, Surrey LF, Vatsky SE, et al. Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF Variant. Pediatr Blood Cancer 2025;72:e32015.

PMID 40884273 PMC12821086 doi:10.1002/pbc.32015 3 reports · GLA · KLA · CCLA

BRAF V600E

Li D, Sheppard SE, March ME, Battig MR, Surrey LF, Srinivasan AS, et al. Genomic profiling informs diagnoses and treatment in vascular anomalies. Nat Med 2023;29:1530-1539.

PMID 37264205 PMC11184491 doi:10.1038/s41591-023-02364-x 26 reports · LM · GLA · KLA · CCLA

PIK3CA E110del PIK3CA R88Q PIK3CA C420R PIK3CA E542K PIK3CA E545K PIK3CA M1043I PIK3CA H1047L PIK3CA H1047R NRAS Q61R HRAS E63_S65delinsDIPP HRAS M72_R73insHSAMRDQYM KRAS G12D KRAS G12V KRAS A146T KRAS Q70_Y71ins15 BRAF V600E MAP2K1 F53C CBL Y774*PIK3CA P447_L455del
Sheppard SE, March ME, Seiler C, Matsuoka LS, Kim SE, Kao C, et al. Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition. JCI Insight 2023;8:e155888.

PMID 37154160 PMC10243805 doi:10.1172/jci.insight.155888 4 reports · CCLA

KRAS G12D KRAS G12V KRAS G13D KRAS A146T

Allen-Rhoades W, Al-Ibraheemi A, Kohorst M, Tollefson M, Hull N, Polites S, et al. Cellular variant of kaposiform lymphangiomatosis: a report of three cases, expanding the morphologic and molecular genetic spectrum of this rare entity. Hum Pathol 2022;122:72-81.

PMID 35202617 doi:10.1016/j.humpath.2022.02.010 2 reports · KLA (cellular)

NRAS Q61K HRAS A59_Q61delinsGGSIL
Zenner K, Jensen DM, Dmyterko V, Shivaram GM, Myers CT, Paschal CR, et al. Somatic activating BRAF variants cause isolated lymphatic malformations. HGG Adv 2022;3:100101.

PMID 35373151 PMC8972000 doi:10.1016/j.xhgg.2022.100101 4 reports · LM

PIK3CA N345K PIK3CA E545K PIK3CA H1047R BRAF V600E

Brouillard P, Schlögel MJ, Homayun Sepehr N, Helaers R, Queisser A, Fastré E, et al. Non-hotspot PIK3CA mutations are more frequent in CLOVES than in common or combined lymphatic malformations. Orphanet J Rare Dis 2021;16:267.

PMID 34112235 PMC8194016 doi:10.1186/s13023-021-01898-y 7 reports · LM

PIK3CA E110del PIK3CA E542K PIK3CA E545G PIK3CA E545K PIK3CA Q546R PIK3CA H1047L PIK3CA H1047R
Homayun-Sepehr N, McCarter AL, Helaers R, Galant C, Boon LM, Brouillard P, et al. KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight 2021;6:149831.

PMID 34156985 PMC8410066 doi:10.1172/jci.insight.149831 1 report · GSD

KRAS G12V
Wang S, Wang W, Zhang X, Gui J, Zhang J, Guo Y, et al. A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation. Orphanet J Rare Dis 2021;16:208.

PMID 33964933 PMC8106842 doi:10.1186/s13023-021-01782-9 2 reports · LM

PIK3CA E545K PIK3CD L666P

Foster JB, Li D, March ME, Sheppard SE, Adams DM, Hakonarson H, et al. Kaposiform lymphangiomatosis effectively treated with MEK inhibition. EMBO Mol Med 2020;12:e12324.

PMID 32894644 PMC7539180 doi:10.15252/emmm.202012324 1 report · KLA

CBL Y774*
Nozawa A, Ozeki M, Niihori T, Suzui N, Miyazaki T, Aoki Y. A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham-Stout disease. J Hum Genet 2020;65:995-1001.

PMID 32591603 doi:10.1038/s10038-020-0794-y 1 report · GSD

KRAS Q61R

Barclay SF, Inman KW, Luks VL, McIntyre JB, Al-Ibraheemi A, Church AJ, et al. A somatic activating NRAS variant associated with kaposiform lymphangiomatosis. Genet Med 2019;21:1517-1524.

PMID 30542204 PMC6565516 doi:10.1038/s41436-018-0390-0 1 report · KLA

NRAS Q61R
Li D, March ME, Gutierrez-Uzquiza A, Kao C, Seiler C, Pinto E, et al. ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nat Med 2019;25:1116-1122.

PMID 31263281 doi:10.1038/s41591-019-0479-2 1 report · CCLA

ARAF S214P
Rodriguez-Laguna L, Agra N, Ibañez K, Ibañez K, Oliva-Molina G, Gordo G, et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J Exp Med 2019;216:407-418.

PMID 30591517 PMC6363432 doi:10.1084/jem.20181353 4 reports · GLA

PIK3CA E542K PIK3CA Q546K PIK3CA H1047L PIK3CA H1047R

Blesinger H, Kaulfuß S, Aung T, Schwoch S, Prantl L, Rößler J, et al. PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations. PLoS One 2018;13:e0200343.

PMID 29985963 PMC6037383 doi:10.1371/journal.pone.0200343 5 reports · LM

PIK3CA E109del PIK3CA C420R PIK3CA E545K PIK3CA Q546K PIK3CA H1047L
Manevitz-Mendelson E, Leichner GS, Barel O, Davidi-Avrahami I, Ziv-Strasser L, Eyal E, et al. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis 2018;21:287-298.

PMID 29397482 doi:10.1007/s10456-018-9595-8 1 report · GLA

NRAS Q61R

Osborn AJ, Dickie P, Neilson DE, Glaser K, Lynch KA, Gupta A, et al. Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations. Hum Mol Genet 2015;24:926-938.

PMID 25292196 doi:10.1093/hmg/ddu505 3 reports · LM

PIK3CA E542K PIK3CA E545A PIK3CA H1047L