Skip to main content
SpringerLink
Log in
Book cover

Lymphedema pp 19–31Cite as

Genetic Causes of Lymphedema

  • Chapter

Abstract

For this chapter, an extensive review of the literature regarding the genes and clinical presentations associated with primary lymphedema is performed. All the signs that have been mentioned for the patients with a proven mutation are catalogued. The phenotypes are divided into two groups depending on whether lymphedema is a primary or a secondary key for diagnosis. This should help clinicians to identify more easily the best candidate gene. Yet, because of the high number of associated genes and the large phenotypic variability, a panel approach to screen all genes at once is likely the most efficient approach for diagnosis.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Balboa-Beltran E, Fernandez-Seara MJ, Perez-Munuzuri A, Lago R, Garcia-Magan C, Couce ML, et al. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J Med Genet. 2014;51(7):475–8.

    Article  CAS  PubMed  Google Scholar 

  2. Gordon K, Spiden SL, Connell FC, Brice G, Cottrell S, Short J, et al. FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. Hum Mutat. 2013;34(1):23–31.

    Article  CAS  PubMed  Google Scholar 

  3. Connell F, Brice G, Jeffery S, Keeley V, Mortimer P, Mansour S. A new classification system for primary lymphatic dysplasias based on phenotype. Clin Genet. 2010;77(5):438–52.

    Article  CAS  PubMed  Google Scholar 

  4. Finegold DN, Kimak MA, Lawrence EC, Levinson KL, Cherniske EM, Pober BR, et al. Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet. 2001;10(11):1185–9.

    Article  CAS  PubMed  Google Scholar 

  5. Ferrell RE, Baty CJ, Kimak MA, Karlsson JM, Lawrence EC, Franke-Snyder M, et al. GJC2 missense mutations cause human lymphedema. Am J Hum Genet. 2010;86(6):943–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Brice G, Ostergaard P, Jeffery S, Gordon K, Mortimer PS, Mansour S. A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family. Clin Genet. 2013;84(4):378–81.

    Article  CAS  PubMed  Google Scholar 

  7. Alders M, Al-Gazali L, Cordeiro I, Dallapiccola B, Garavelli L, Tuysuz B, et al. Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet. 2014;133(9):1161–7.

    Article  CAS  PubMed  Google Scholar 

  8. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Kawai T, Nishikomori R, Heike T. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergol Int. 2012;61(2):207–17.

    Article  CAS  PubMed  Google Scholar 

  10. Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, et al. Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans. Am J Hum Genet. 2010;87(3):436–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, et al. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet. 2003;72(6):1470–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, et al. Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene. Clin Genet. 2014. Article first published online: 16 APR 2014, DOI: 10.1111/cge.12388.

    Google Scholar 

  13. Geffrey AL, Shinnick JE, Staley BA, Boronat S, Thiele EA. Lymphedema in tuberous sclerosis complex. Am J Med Genet A. 2014;164A(6):1438–42.

    Article  PubMed  Google Scholar 

  14. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126(4):746–59.

    Article  PubMed  Google Scholar 

  16. Sybert VP, McCauley E. Turner’s syndrome. N Engl J Med. 2004;351(12):1227–38.

    Article  CAS  PubMed  Google Scholar 

  17. Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34(12):1632–41.

    Article  CAS  PubMed  Google Scholar 

  18. Burrows PE, Gonzalez-Garay ML, Rasmussen JC, Aldrich MB, Guilliod R, Maus EA, et al. Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. Proc Natl Acad Sci U S A. 2013;110(21):8621–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Mendola A, Schlogel MJ, Ghalamkarpour A, Irrthum A, Nguyen HL, Fastre E, et al. Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema. Mol Syndromol. 2013;4(6):257–66.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Lepri FR, Scavelli R, Digilio MC, Gnazzo M, Grotta S, Dentici ML, et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014;15:14.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest. 2014;124(3):898–904.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Ivanov KI, Agalarov Y, Valmu L, Samuilova O, Liebl J, Houhou N, et al. Phosphorylation regulates FOXC2-mediated transcription in lymphatic endothelial cells. Mol Cell Biol. 2013;33(19):3749–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Wu YH, Hu TF, Chen YC, Tsai YN, Tsai YH, Cheng CC, et al. The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility. Blood. 2011;118(10):2896–905.

    Article  CAS  PubMed  Google Scholar 

  24. Sevick-Muraca EM, King PD. Lymphatic vessel abnormalities arising from disorders of Ras signal transduction. Trends Cardiovasc Med. 2014;24(3):121–7.

    Article  CAS  PubMed  Google Scholar 

  25. Moncrieff M, Shannon K, Hong A, Hersey P, Thompson J. Dramatic reduction of chronic lymphoedema of the lower limb with sorafenib therapy. Melanoma Res. 2008;18(2):161–2.

    Article  PubMed  Google Scholar 

  26. Honkonen KM, Visuri MT, Tervala TV, Halonen PJ, Koivisto M, Lahteenvuo MT, et al. Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema. Ann Surg. 2013;257(5):961–7.

    Article  PubMed  Google Scholar 

  27. Saito Y, Nakagami H, Morishita R, Takami Y, Kikuchi Y, Hayashi H, et al. Transfection of human hepatocyte growth factor gene ameliorates secondary lymphedema via promotion of lymphangiogenesis. Circulation. 2006;114(11):1177–84.

    Article  CAS  PubMed  Google Scholar 

  28. Finegold DN, Baty CJ, Knickelbein KZ, Perschke S, Noon SE, Campbell D, et al. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Clin Cancer Res. 2012;18(8):2382–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Miaskowski C, Dodd M, Paul SM, West C, Hamolsky D, Abrams G, et al. Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery. PLoS One. 2013;8(4):e60164.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Matthieu J. Schlögel M.Sc., Pascal Brouillard Ph.D. & Miikka Vikkula M.D., Ph.D.

  2. Cliniques universitaires Saint-Luc, Center for Vascular Anomalies, Universite catholique de Louvain, Brussels, Belgium

    Laurence M. Boon M.D., Ph.D.

  3. Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Brussels, Belgium

    Miikka Vikkula M.D., Ph.D.

Authors
  1. Matthieu J. Schlögel M.Sc.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pascal Brouillard Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurence M. Boon M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miikka Vikkula M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miikka Vikkula M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA

    Arin K. Greene

  2. Division of Plastic Surgery, Beth Israel Deaconess Medical Center, Brookline, Massachusetts, USA

    Sumner A. Slavin

  3. Plastic and Reconstructive Surgery, Skåne University Hospital, Malmö, Sweden

    Håkan Brorson

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Schlögel, M.J., Brouillard, P., Boon, L.M., Vikkula, M. (2015). Genetic Causes of Lymphedema. In: Greene, A., Slavin, S., Brorson, H. (eds) Lymphedema. Springer, Cham. https://doi.org/10.1007/978-3-319-14493-1_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-14493-1_3

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-14492-4

  • Online ISBN: 978-3-319-14493-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation