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Molecular Genetics of Lymphatic and Complex Vascular Malformations

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Lymphedema

Abstract

Lymphatic malformations (LMs) are due to localized defects in lymphatic development. They usually occur sporadically. There is an important heterogeneity in clinical presentations. LMs can affect any part of the body, be isolated, or be part of a syndrome. They can present as pure or combined lesions. Lymphaticovenous malformation (LVM) is a common example of the latter. They most often cause pain, dysfunction of the affected body part, and disfigurement. Elucidation of the etiopathogenesis of LMs had to wait for the development of next-generation sequencing (NGS) used on endothelial cells isolated from lymphatic malformations or directly on resected lesions. This allowed to discover somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). The mutations are similar to those identified in cancers, venous malformations (VMs), and combined vascular lesions, including the spectrum of PIK3CA-related overgrowth syndromes (PROS). The phenotypic variability is most likely due to differences in developmental time point and type(s) of cells in which the somatic mutations occurred. Some related syndromes are also caused by activating mutations in the PI3K-AKT-mTOR signaling pathway, including Proteus syndrome (mutations in AKT1) and PTEN hamartoma tumor syndrome (mutations in PTEN). This has opened the era for development of targeted precision therapies for these lesions, especially by using small molecule inhibitors. Rapamycin, an inhibitor of mTOR, has already been tested in clinical trials and four studies (78 patients) demonstrated efficacy on selected cases.

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Acknowledgments

We are grateful to all the family members for their invaluable contributions. These studies were partially supported by the Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) program through the project IAP P7/43-BeMGI, the Fonds de la Recherche Scientifique - FNRS, T.0026.14 (to MV) and T.0146.16 (to LMB), and the Fonds de la Recherche Scientifique - FNRS for the FRFS-WELBIO under Grant n° WELBIO-CR-2015A (to MV). We also acknowledge the support of Fédération Wallonie-Bruxelles, la Lotterie nationale, Belgium, and the Foundation against Cancer, Belgium. P.B. is a Senior Platform Manager of UCL. M. S. was supported by a fellowship from F.R.I.A. (Fonds pour la formation à la recherche dans l’industrie et dans l’agriculture). The authors thank the Genomics Plateform of Université catholique de Louvain and Ms. Liliana Niculescu for secretarial help.

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Authors and Affiliations

  1. Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    Matthieu J. Schlögel, Pascal Brouillard, Laurence M. Boon & Miikka Vikkula MD, PhD

  2. Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

    Laurence M. Boon & Miikka Vikkula MD, PhD

  3. Walloon Excellence in Life sciences and Biotechnology (WELBIO), Université catholique de Louvain, Brussels, Belgium

    Miikka Vikkula MD, PhD

Authors
  1. Matthieu J. Schlögel
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  2. Pascal Brouillard
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  3. Laurence M. Boon
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  4. Miikka Vikkula MD, PhD
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Corresponding author

Correspondence to Miikka Vikkula MD, PhD .

Editor information

Editors and Affiliations

  1. Center for the Lymphedema and Vascular Malformations, Division of Vascular Surgery, Department of Surgery, George Washington University, Washington, DC, USA

    Byung-Boong Lee

  2. Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, California, USA

    Stanley G. Rockson

  3. La Jolla, California, USA

    John Bergan

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Schlögel, M.J., Brouillard, P., Boon, L.M., Vikkula, M. (2018). Molecular Genetics of Lymphatic and Complex Vascular Malformations. In: Lee, BB., Rockson, S., Bergan, J. (eds) Lymphedema. Springer, Cham. https://doi.org/10.1007/978-3-319-52423-8_60

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  • DOI: https://doi.org/10.1007/978-3-319-52423-8_60

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-52421-4

  • Online ISBN: 978-3-319-52423-8

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