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Primary lymphoedema

Abstract

Lymphoedema is the swelling of one or several parts of the body owing to lymph accumulation in the extracellular space. It is often chronic, worsens if untreated, predisposes to infections and causes an important reduction in quality of life. Primary lymphoedema (PLE) is thought to result from abnormal development and/or functioning of the lymphatic system, can present in isolation or as part of a syndrome, and can be present at birth or develop later in life. Mutations in numerous genes involved in the initial formation of lymphatic vessels (including valves) as well as in the growth and expansion of the lymphatic system and associated pathways have been identified in syndromic and non-syndromic forms of PLE. Thus, the current hypothesis is that most cases of PLE have a genetic origin, although a causative mutation is identified in only about one-third of affected individuals. Diagnosis relies on clinical presentation, imaging of the structure and functionality of the lymphatics, and in genetic analyses. Management aims at reducing or preventing swelling by compression therapy (with manual drainage, exercise and compressive garments) and, in carefully selected cases, by various surgical techniques. Individuals with PLE often have a reduced quality of life owing to the psychosocial and lifelong management burden associated with their chronic condition. Improved understanding of the underlying genetic origins of PLE will translate into more accurate diagnosis and prognosis and personalized treatment.

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Fig. 1: Examples of primary lymphoedema.
Fig. 2: Schematic of the spectrum of pathological findings in PLEs.
Fig. 3: Loci, genes and proteins associated with PLE.
Fig. 4: Recurrent manifestations associated with rare syndromic PLEs.
Fig. 5: Proposed classification of lymphatic anomaly phenotypes.
Fig. 6: Non-surgical and surgical treatments of PLE.

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Acknowledgements

M.V.’s laboratories were financially supported by the Fonds de la Recherche Scientifique – FNRS Grants T.0026.14 and T.0247.19, the Fund Generet managed by the King Baudouin Foundation (Grant 2018-J1810250-211305), and by la Région wallonne dans le cadre du financement de l’axe stratégique FRFS-WELBIO (WELBIO-CR-2019C-06). M.V. has also received funding from the MSCA-ITN network V. A. Cure No. 814316 and the Lymphatic Malformation Institute, USA. M.H.W. has received research support from the University of Arizona Health Sciences Translational Imaging Program Projects Stimulus (TIPPS) Award and National Institutes of Health NHLBI R25HL108837 for diverse undergraduate research trainees (Luis Luy, Jasmine Jones, Reginald Myles); she is also Secretary-General, International Society of Lymphology, Tucson, AZ, USA, and Zurich, Switzerland. The authors are grateful to Grace Wagner and Juan Ruiz for programmatic assistance and to Liliana Niculescu for expert secretarial assistance.

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Introduction (M.V., P.B., M.H.W. and R.P.E.); Epidemiology (M.V., P.B., M.H.W., R.P.E. and I.Q.); Mechanisms/pathophysiology (M.V., P.B., M.H.W., R.P.E. and I.Q.); Diagnosis, screening and prevention (M.V., P.B., M.H.W., R.P.E., R.J.D., C.B. and I.Q.); Management (M.V., P.B., M.H.W., R.P.E., C.B. and I.Q.); Quality of life (M.V., P.B., M.H.W., R.P.E., R.J.D. and I.Q.); Outlook (M.V., P.B., M.H.W., R.P.E. and I.Q.); Overview of Primer (M.V.).

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Correspondence to Miikka Vikkula.

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Brouillard, P., Witte, M.H., Erickson, R.P. et al. Primary lymphoedema. Nat Rev Dis Primers 7, 77 (2021). https://doi.org/10.1038/s41572-021-00309-7

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