Lymphedema pp 765-775 | Cite as

Syndromic Lymphedema and Complex Vascular Malformations with Lymphatic Involvement

  • Francine BleiEmail author


  • Many syndromes have lymphedema as a predominant clinical feature.

  • Somatic and genomic mutations have been identified in several of these syndromes, providing insight into the pathophysiology of these disorders.

  • This chapter reviews the lymphedema syndromes and the involved genes and affected pathways.


Lymphedema Syndromes International Society For The Study Of Vascular Anomalies (ISSVA) Emberger Syndrome Protein Tyrosine Phosphatase Nonreceptor Type (PTPN11) PIK3CA-related Overgrowth Spectrum (PROS) 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Highlighted References

  1. 1.
    Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet. 2013;84(4):303–14.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest. 2014;124(3):898–904.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015;167A(2):287–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013;105(21):1607–16.CrossRefPubMedGoogle Scholar


  1. 6.
    Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, et al. Vascular anomalies classification: recommendations from the International Society for the Study of vascular anomalies. Pediatrics. 2015;136(1):e203–14.CrossRefPubMedGoogle Scholar
  2. 7.
    Crawford J, Bower NI, Hogan BM, Taft RJ, Gabbett MT, McGaughran J, et al. Expanding the genotypic spectrum of CCBE1 mutations in Hennekam syndrome. Am J Med Genet A. 2016 170(10): 2694-2697.Google Scholar
  3. 8.
    Kratz CP, Franke L, Peters H, Kohlschmidt N, Kazmierczak B, Finckh U, et al. Cancer Spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br J Cancer. 2015;112(8):1392–7.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 9.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 10.
    Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P, Le J, Wallenstein MB, Milla C, et al. RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet A. 2016;170(6):1450–4.CrossRefPubMedGoogle Scholar
  6. 11.
    Boudon E, Levy Y, Abossolo T, Cartault F, Brouillard P, Vikkula M, et al. Antenatal presentation of hereditary lymphedema type I. Eur J Med Genet. 2015;58(6–7):329–31.CrossRefPubMedGoogle Scholar
  7. 12.
    Ma GC, Liu CS, Chang SP, Yeh KT, Ke YY, Chen TH, et al. A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy. Prenat Diagn. 2008;28(11):1057–63.CrossRefPubMedGoogle Scholar
  8. 13.
    Kang HC, Baek ST, Song S, Gleeson JG. Clinical and genetic aspects of the segmental overgrowth Spectrum due to somatic mutations in PIK3CA. J Pediatr. 2015;167(5):957–62.CrossRefPubMedGoogle Scholar
  9. 14.
    Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011;365(7):611–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 15.
    Maclellan RA, Chaudry G, Greene AK. Combined Lymphedema and capillary malformation of the lower extremity. Plast Reconstr Surg Glob Open. 2016;4(2):e618.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 16.
    Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol. 2010;1(1):2–26.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 17.
    Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25(1):161–79.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 18.
    Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011;32(7):760–72.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 19.
    Smpokou P, Tworog-Dube E, Kucherlapati RS, Roberts AE. Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome. Am J Med Genet A. 2012;158A(12):3106–11.CrossRefPubMedGoogle Scholar
  15. 20.
    Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet. 2000;25(2):153–9.CrossRefPubMedGoogle Scholar
  16. 21.
    Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet. 2000;67(2):295–301.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 22.
    Ghalamkarpour A, Debauche C, Haan E, Van Regemorter N, Sznajer Y, Thomas D, et al. Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2. J Pediatr. 2009a;155(1):90–3.CrossRefPubMedGoogle Scholar
  18. 23.
    Ghalamkarpour A, Holnthoner W, Saharinen P, Boon LM, Mulliken JB, Alitalo K, et al. Recessive primary congenital lymphoedema caused by a VEGFR3 mutation. J Med Genet. 2009b;46(6):399–404.CrossRefPubMedGoogle Scholar
  19. 24.
    Malik S, Grzeschik KH. Congenital, low penetrance lymphedema of lower limbs maps to chromosome 6q16.2-q22.1 in an inbred Pakistani family. Hum Genet. 2008;123(2):197–205.CrossRefPubMedGoogle Scholar
  20. 25.
    Gordon K, Schulte D, Brice G, Simpson MA, Roukens MG, van Impel A, et al. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Circ Res. 2013;112(6):956–60.CrossRefPubMedGoogle Scholar
  21. 26.
    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.CrossRefPubMedGoogle Scholar
  22. 27.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 28.
    Ostergaard P, Simpson MA, Brice G, Mansour S, Connell FC, Onoufriadis A, et al. Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J Med Genet. 2011a;48(4):251–5.CrossRefPubMedGoogle Scholar
  24. 29.
    Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, et al. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet. 2002;39(7):478–83.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 30.
    Fabretto A, Shardlow A, Faletra F, Lepore L, Hladnik U, Gasparini P. A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation. Ophthalmic Genet. 2010;31(2):98–100.CrossRefPubMedGoogle Scholar
  26. 31.
    Fauret AL, Tuleja E, Jeunemaitre X, Vignes S. A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasis syndrome. Lymphology. 2010;43(1):14–8.PubMedGoogle Scholar
  27. 32.
    Mellor RH, Tate N, Stanton AW, Hubert C, Makinen T, Smith A, et al. Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency. J Vasc Res. 2011;48(5):397–407.CrossRefPubMedGoogle Scholar
  28. 33.
    Sutkowska E, Gil J, Stembalska A, Hill-Bator A, Szuba A. Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema-distichiasis syndrome. Gene. 2012;498(1):96–9.CrossRefPubMedGoogle Scholar
  29. 34.
    Itoh M, Kawagoe S, Okano HJ, Nakagawa H. Integration-free T cell-derived human induced pluripotent stem cells (iPSCs) from a patient with lymphedema-distichiasis syndrome (LDS) carrying an insertion-deletion complex mutation in the FOXC2 gene. Stem Cell Res. 2016;16(3):611–3.CrossRefPubMedGoogle Scholar
  30. 35.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 36.
    Downes M, Francois M, Ferguson C, Parton RG, Koopman P. Vascular defects in a mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation. Hum Mol Genet. 2009;18(15):2839–50.CrossRefPubMedGoogle Scholar
  32. 37.
    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. 2015;87(4):378–82.CrossRefPubMedGoogle Scholar
  33. 38.
    Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012;90(2):356–62.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 39.
    Hazan F, Ostergaard P, Ozturk T, Kantekin E, Atlihan F, Jeffery S, et al. A novel KIF11 mutation in a Turkish patient with microcephaly, lymphedema, and chorioretinal dysplasia from a consanguineous family. Am J Med Genet A. 2012;158A(7):1686–9.CrossRefPubMedGoogle Scholar
  35. 40.
    Schlögel J, Mendola A, Fastré E, Vasudevan P, Devriendt K, de Ravel TJL, Van Esch H, Casteels I, Carrera IA, Cristofoli F, Fieggen K, Jones K, Lipson M, Balikova I, Singer A, Soller M, Villanueva MM, Revencu N, Boon LM, Brouillard P, Vikkulac M. No locus heterogeneity in familial Microcephaly with or without Chorioretinopathy, Lymphedema, or mental retardation syndrome. Orphanet J. 2015;10:52. Scholar
  36. 41.
    Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, et al. Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases. Am J Med Genet A. 2010;152A(9):2287–96.CrossRefPubMedGoogle Scholar
  37. 42.
    Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011b;43(10):929–31.CrossRefPubMedGoogle Scholar
  38. 43.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 44.
    Kreuter A, Hochdorfer B, Brockmeyer NH, Altmeyer P, Pfister H, Wieland U. A human papillomavirus-associated disease with disseminated warts, depressed cell-mediated immunity, primary lymphedema, and anogenital dysplasia: WILD syndrome. Arch Dermatol. 2008;144(3):366–72.CrossRefPubMedGoogle Scholar
  40. 45.
    Hennekam RC, Geerdink RA, Hamel BC, Hennekam FA, Kraus P, Rammeloo JA, et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet. 1989;34(4):593–600.CrossRefPubMedGoogle Scholar
  41. 46.
    Van Balkom ID, Alders M, Allanson J, Bellini C, Frank U, De Jong G, et al. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet. 2002;112(4):412–21.CrossRefPubMedGoogle Scholar
  42. 47.
    Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet. 2009;41(12):1272–4.CrossRefPubMedGoogle Scholar
  43. 48.
    Alders M, Mendola A, Ades L, Al Gazali L, Bellini C, Dallapiccola B, et al. Evaluation of clinical manifestations in patients with severe Lymphedema with and without CCBE1 mutations. Mol Syndromol. 2013;4(3):107–13.PubMedGoogle Scholar
  44. 49.
    Bull LN, Roche E, Song EJ, Pedersen J, Knisely AS, van Der Hagen CB, et al. Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q. Am J Hum Genet. 2000;67(4):994–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 50.
    Fruhwirth M, Janecke AR, Muller T, Carlton VE, Kronenberg F, Offner F, et al. Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome. J Pediatr. 2003;142(4):441–7.CrossRefPubMedGoogle Scholar
  46. 51.
    Roberts CM, Angus JE, Leach IH, McDermott EM, Walker DA, Ravenscroft JC. A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency (OL-HED-ID). Eur J Pediatr. 2010;169(11):1403–7.CrossRefPubMedGoogle Scholar
  47. 52.
    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.CrossRefPubMedGoogle Scholar
  48. 53.
    Durr HR, Pellengahr C, Nerlich A, Baur A, Maier M, Jansson V. Stewart-Treves syndrome as a rare complication of a hereditary lymphedema. Vasa. 2004;33(1):42–5.CrossRefPubMedGoogle Scholar
  49. 54.
    Komorowski AL, Wysocki WM, Mitus J. Angiosarcoma in a chronically lymphedematous leg: an unusual presentation of Stewart-Treves syndrome. South Med J. 2003;96(8):807–8.CrossRefPubMedGoogle Scholar
  50. 55.
    Morcaldi G, Bellini T, Rossi C, Maghnie M, Boccardo F, Bonioli E, et al. Lymphodysplasia and Kras mutation: a case report and literature review. Lymphology. 2015;48(3):121–7.PubMedGoogle Scholar
  51. 56.
    Lo IF, Brewer C, Shannon N, Shorto J, Tang B, Black G, et al. Severe neonatal manifestations of Costello syndrome. J Med Genet. 2008;45(3):167–71.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.New YorkUSA

Personalised recommendations