Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Special Article
  • Published:

Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition

Abstract

Background

Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy.

Methods

The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay.

Results

Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib.

Conclusions

Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies.

Impact

  • This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation.

  • Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies.

  • We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis.

  • Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Effect of trametinib on platelet counts, pulmonary function tests, and radiographic appearance.
Fig. 2: In vitro studies of trametinib on the activity of mutant NRAS-expressing cells.

Similar content being viewed by others

References

  1. Croteau, S. E. et al. Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly. J. Pediatr. 164, 383–388 (2014).

    Article  PubMed  Google Scholar 

  2. Bundy, J. J. et al. Thoracic duct embolization in Kaposiform lymphangiomatosis. J. Vasc. Surg. Venous Lymphat. Disord. 8, 864–868 (2020).

    Article  PubMed  Google Scholar 

  3. Ozeki, M. & Fukao, T. Generalized lymphatic anomaly and Gorham-Stout disease: overview and recent insights. Adv. Wound Care 8, 230–245 (2019).

    Article  Google Scholar 

  4. Crane, J. et al. Kaposiform lymphangiomatosis treated with multimodal therapy improves coagulopathy and reduces blood angiopoietin-2 levels. Pediatr. Blood Cancer 67, e28529 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Boscolo, E. et al. Signaling pathways and inhibitors of cells from patients with Kaposiform lymphangiomatosis. Pediatr. Blood Cancer 66, e27790 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Manevitz-Mendelson, E. et al. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis 21, 287–298 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Barclay, S. F. et al. A somatic activating NRAS variant associated with Kaposiform lymphangiomatosis. Genet. Med. 21, 1517–1524 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Ozeki, M. et al. Detection of NRAS mutation in cell-free DNA biological fluids from patients with Kaposiform lymphangiomatosis. Orphanet J. Rare Dis. 14, 215 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Foster, J. B. et al. Kaposiform lymphangiomatosis effectively treated with MEK inhibition. EMBO Mol. Med. 12, e12324 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dori, Y. et al. Severe lymphatic disorder resolved with MEK inhibition in a patient with Noonan syndrome and Sos1 mutation. Pediatrics 146, e20200167 (2020).

  11. Li, D. et al. Araf recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nat. Med. 25, 1116–1122 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Wang, Z. et al. Successful treatment of Kaposiform lymphangiomatosis with sirolimus. Pediatr. Blood Cancer 62, 1291–1293 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Zhou, J., Yang, K., Chen, S. & Ji, Y. Sirolimus in the treatment of Kaposiform lymphangiomatosis. Orphanet J. Rare Dis. 16, 260 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Adams, D. M. et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics 137, e20153257 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ricci, K. W. & Iacobas, I. How we approach the diagnosis and management of complex lymphatic anomalies. Pediatr. Blood Cancer e28985 (2021).

  16. Bhagwat, S. V. et al. Preclinical characterization of Osi-027, a potent and selective inhibitor of Mtorc1 and Mtorc2: distinct from rapamycin. Mol. Cancer Ther. 10, 1394–1406 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Nozawa, A. et al. Characterization of Kaposiform lymphangiomatosis tissue-derived cells. Pediatr. Blood Cancer e29086 (2021).

  18. Glaser, K., Dickie, P. & Dickie, B. H. Proliferative cells from Kaposiform lymphangiomatosis lesions resemble mesenchyme stem cell-like pericytes defective in vessel formation. J. Pediatr. Hematol. Oncol. 40, e495–e504 (2018).

    Article  PubMed  Google Scholar 

  19. Seo, S. K., Suh, J. C., Na, G. Y., Kim, I. S. & Sohn, K. R. Kasabach-Merritt syndrome: identification of platelet trapping in a tufted angioma by immunohistochemistry technique using monoclonal antibody to Cd61. Pediatr. Dermatol. 16, 392–394 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Homayun-Sepehr, N. et al. KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight 6, e149831 (2021).

  21. Ryan, M. B. & Corcoran, R. B. Therapeutic strategies to target Ras-mutant cancers. Nat. Rev. Clin. Oncol. 15, 709–720 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Dummer, R. et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (Nemo): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 18, 435–445 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Greenberger, S. et al. Agminated benign vascular tumour successfully treated with trametinib. Br. J. Dermatol. 184, 1195–1197 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Research reported in this publication was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number 1R21TR003331 (to D.L. and M.M.).

Author information

Authors and Affiliations

Authors

Contributions

G.C., A.D., G.A.-C., and H.G. conceived and designed the study. G.C., G.A.-C., H.G., A.V., S.G., M.S., G.B., I.F.-F., D.L., M.M., M.R.B., H.H., D.A., and A.D. acquired, analyzed, and interpreted the data. G.C. drafted the manuscript. All authors revised and approved the manuscript.

Corresponding author

Correspondence to Adi Dagan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All studies were performed following the patient’s informed consent and according to the principles of the Declaration of Helsinki. Approval was obtained from Sheba Medical Center Institutional Review Board.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chowers, G., Abebe-Campino, G., Golan, H. et al. Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition. Pediatr Res 94, 1911–1915 (2023). https://doi.org/10.1038/s41390-022-01986-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-022-01986-0

This article is cited by

Search

Quick links