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Last updated: 3/26/2024
Years published: 1986, 1987, 1989, 1990, 1994, 1999, 2006, 2008, 2012, 2015, 2022, 2024
NORD gratefully acknowledges R. Carson Sibley, MD, Deborah Crow-Petree, PhD, RN, and Heather Ferguson, Executive Director, Lymphedema Advocacy Group; and Beatriz Anguiano, MS, Kirsten Blanco, MS, Malika K. Freund, PhD, and MaryAnn Campion, EdD, MS, CGC, from the Stanford University MS Program in Human Genetics and Genetic Counseling for assistance in the preparation of this report.
Summary
Primary lymphedema is a genetic condition affecting the lymphatic system and is characterized by chronic swelling (edema) of affected parts of the body, usually most commonly the lower limbs. The lymphatic system is an extensive network of vessels, nodes and ducts involved in whole body fluid homeostasis and immune cell trafficking, and lipid absorption in the gut. Errors in development may result in underdevelopment (hypoplasia/aplasia) or overgrowth (hyperplasia) of lymphatic vessels. The malformed vessels lack capacity to collect and return lymph to the venous circulation and protein-rich fluid accumulates in the subcutaneous tissues under the outermost layer of skin (epidermis) of the affected area. This leads to swelling (lymphedema) that may result in mild (< 20%) to severe (> 40%) enlargement of affected limbs. An inflammatory process, stimulated by the retained fluid, causes changes in the quality of the surface of the skin, thickening or hardening of the tissues (fibrosis) and stimulation of fat (adipose) deposition. Psychological distress related to appearance and necessary self-management practices is common. There is no cure for primary lymphedema. However, an effective compression regimen, active lifestyle and maintenance of normal body weight will limit progression of the condition.
Primary lymphedema is caused by abnormalities in lymphatic vasculature presumably due to disease-causing genetic variants. Most (70%) individuals with primary lymphedema have a condition that occurs sporadically (irregularly) with no known family history and/or confirmed genetic variant. In some patients, lymphedema may be the only clinical feature while in others lymphedema may be the main or a minor clinical feature of a multisystem disorder (syndrome) and may be present in systemic conditions involving internal organs and structures (complex lymphatic anomaly).
In contrast, secondary lymphedema is an acquired condition resulting from damage from surgery, tumor, radiation therapy, trauma or infection in the absence of any anatomical abnormalities.
Introduction
Historically, primary lymphedema has been characterized by age of onset: type I (congenital or up to 2 years of age); type II lymphedema praecox (from 2 to 35 years of age) and lymphedema tarda (after 35 years of age). Medical experts now recommend describing the onset of symptoms using developmental terms such as infancy, childhood, adolescence and adulthood. Congenital-onset (or infancy) primary lymphedema may be associated with variants in the FLT4 gene, while primary lymphedema occurring later, usually near adolescence, has been associated with variants in the FOXC2 gene. Currently, most patients with primary lymphedema are not diagnosed with a disease-causing gene variant. Many new target genes have recently been identified, and research is ongoing.
The main symptom associated with primary lymphedema is edema in different parts of the body due to accumulation of lymph in the soft layers of tissue under the epidermis. Swelling frequently occurs in one or both legs, but may also be present in the trunk, face, genitalia and arms. When lymphedema develops in the arms or legs, swelling is usually most noticeable furthest from the heart (distally) but may involve the whole limb. In some people, swelling may cause sensations of tightness, heaviness, discomfort and unusual tingling (paresthesia) in the affected areas. The affected area heals poorly even after minor trauma (e.g., cut or insect bite). The skin of the affected area may become abnormally dry and scaly (hyperkeratosis) and fibroadipose tissue may form beneath the skin resulting in deep fissures and a โwoodyโ texture. Other skin problems may develop such as bleeding from fluid-filled sacs (vesicles), leakage of lymph fluid from the skin (lymphorrhea), and warty growth (papillomatosis).
Conditions associated with lymphedema that is present at or shortly after birth (< 1 year), most often affect the legs (90%), and in some patients, the genitals may also be affected. The extent and location of edema varies greatly from person to person even among individuals in the same family. Ultrasound scanning during pregnancy may indicate if a fetus is affected if swelling of the tops (dorsum) of the feet is noted in the second or third trimester. Additional clinical features include upslanting, dysplastic toenails, and large or prominent veins below the knees and in males, urethral abnormalities and the development of a fluid-filled sac along the spermatic cord of the scrotum (hydrocele).
Conditions associated with primary lymphedema that develops after one year of age may include swelling that is unilateral, bilateral or involve all four limbs and sometimes the genitalia. Some individuals may present with unilateral swelling, but the opposite, corresponding (contralateral) limb may become involved later (9 to 25% risk) and show abnormalities on an imaging study (radionuclide lymphoscintigraphy) even when edema cannot be observed.
Affected individuals with lymphedema are at risk for developing infections including cellulitis or infection of the lymphatic vessels (lymphangitis). Bacterial infection of the skin and underlying soft tissues (cellulitis) has also been reported in approximately 20% of individuals with primary lymphedema. These infections are characterized by areas of warm, painful and reddened skin. Red skin โstreaksโ may also develop in the infected area. Increased edema is common. A general feeling of ill health (malaise), fever, chills and/or headaches may also occur. If left untreated, cellulitis can lead to septicemia, skin abscesses, areas of ulceration and/or tissue damage (necrosis). Athleteโs foot (tinea pedis) can cause cracks in the interdigital skin, bacterial invasion, and then cellulitis.
Individuals affected with lymphedema are at a greater risk than the general population for developing a non-melanoma skin cancer at the affected site. These malignancies include angiosarcoma, which are cancerous tumors that develop from blood or lymphatic vessels. A rare type of angiosarcoma is known as lymphangiosarcoma, or Stewart-Treves syndrome (STS). STS has been reported in long-standing cases of primary lymphedema. STS occurs in the lymphedematous extremity but can spread to the adjacent trunk and lungs.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Variants in more than 20 genes have been identified as causing primary lymphedema as an isolated clinical feature or as part of a syndrome or complex lymphatic anomaly, and research continues about other possible genetic causes.
Autosomal dominant genetic conditions occur when only a single copy of a disease-causing gene variant is necessary to cause a particular disease. The variant can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Milroy disease, a congenital-onset primary lymphedema, is caused by variants in the FMS-like tyrosine kinase 4 (FLT4) gene. The FLT4 gene provides instructions to make a protein called vascular endothelial growth factor receptor 3 (VEGFR-3) that regulates the development and maintenance of the lymphatic system. Most individuals diagnosed with Milroy disease have an affected parent demonstrating an autosomal dominant inheritance pattern, though approximately 10% may have the disorder due to a non-inherited (de novo) FLT4 gene variant. Approximately 85%-90% of individuals with a FLT4 variant will develop edema in both lower extremities by 1 year of age, while 10%-15% will show no signs or symptoms of lymphedema (reduced penetrance). Types and severity of symptoms can vary widely even within the same family (variable expressivity).
Meige disease is the most common type of primary lymphedema. This disease follows an autosomal inheritance pattern and is associated with missense variants in the GJC2 gene. Meige disease develops in the lower limbs around puberty or shortly thereafter in most individuals and is not associated with any other symptoms.
Primary lymphedema affects approximately 1.15 in 100,000 individuals < 20 years old. Primary lymphedema affects females more often than males, with a ratio of 3.5/1. Primary lymphedema during adolescence is more common among girls while boys are more commonly affected during infancy. Worsening lymphedema during hormonal changes associated with puberty, menses and pregnancy may explain the gender difference.
Primary lymphedema confined to the limbs can be diagnosed through clinical evaluation ninety percent of the time. For example, inability to pinch the skin on the dorsum of the foot (Stemmer sign) is fairly sensitive (92%) and specific (56%) for the condition. Radionuclide lymphoscintigraphy is the definitive imaging study for diagnosis of primary lymphedema. During lymphoscintigraphy, a radioactively labeled colloid substance (tracer) is injected through the skin (intradermally) into either the hands or feet and monitored as it is transported through the body. The time required for the tracer to be transported from the point of injection to the regional lymph nodes is recorded. Findings suggestive of primary lymphedema include delayed transit time, dermal backflow (accumulation of tracer in the lymphatics of the skin), asymmetrical uptake in the lymph nodes, formation of collateral lymphatic channels, and pathological uptake by lymph nodes deep in the elbow or knee areas. In congenital-onset primary lymphedema, the tracer may not move at all from the site of injection.
Other specialized imaging approaches include using reflected sound waves to create images (ultrasound) or magnetic field and radio waves to produce cross-sectional images (magnetic resonance imaging, MRI). A Doppler ultrasound can evaluate venous conditions such as varicose veins and venous blood clots. An MRI can detect findings characteristic of primary lymphedema including edema, a mass surrounded by a sac containing lymph fluid (lymphocele) and the formation of fibrous tissue (fibrosis).
For Milroy disease, a diagnosis can be made via clinical evaluation identifying lymphedema in the lower limbs before age one and either (1) molecular genetic testing identifying a disease-causing variant in the FLT4 gene or (2) lymphoscintigraphy showing reduced tracer movement. Because lymphedema can also be a part of many other conditions and may be the first symptom to appear, genetic testing can sometimes distinguish between a diagnosis of primary lymphedema and other inherited disorders.
Treatment
For most individuals with primary lymphedema affecting the limbs, conservative treatment including compression regimens, exercise, maintenance of normal body weight and avoiding infection may be the best management. Compression regimens include compression garments chosen in consultation with a physician and/or therapist. A compression regimen may also include use of a pneumatic compression pump. The pump, using an electric power source, delivers intermittent compression while the affected limb(s), and sometimes the thorax, are inserted into an inflatable sleeve(s). Other lymphedema self-management โtoolsโ may include short-stretch bandages, adjustable compression wraps, compression foam sleeves, and/or night-time garments that apply milder pressure than compression garments worn during the day.
Complete decongestive therapy (CDT), conducted by a certified lymphedema therapist, may be recommended to reduce the volume of edema in the limb(s) over a few weeks. CDT is a form of treatment in which specialized manual techniques (manual lymph drainage) are combined with multi-layered compression bandaging, meticulous skin care and exercise. CDT concludes with the fitting of compression garments that will maintain the effects of CDT. Rehabilitation therapy may be necessary in cases where extreme lymphedema impairs daily activities.
For individuals who are unable to achieve satisfactory management of their lymphedema with conservative therapy and have excess subcutaneous adipose tissue, suction-assisted lipectomy effectively reduces limb volume, increases cutaneous blood flow, reduces the risk of cellulitis and improves quality of life. Continued use of compression garments is still necessary. The role of microvascular procedures, such as lymphatic-venous anastomosis and lymph node transfer, is unclear for people with primary lymphedema.
To prevent progression of edema, individuals with primary lymphedema are encouraged to live an active lifestyle and avoid long periods of immobility with their legs placed in a downward position at a level lower than the heart (dependent position) and reduce excessive salt intake to reduce flid retention. Body mass index (BMI) predicts morbidity and obese individuals with primary lymphedema are more likely to suffer infections, have larger extremities and experience disability. Calcium channel blocking drugs and non-steroidal anti-inflammatory drugs (NSAIDs) have been known to worsen edema in the lower limbs in the standard population and the benefits and risks of using these medications should be thoroughly discussed with a physician. Diuretics are of limited use in the treatment of primary lymphedema, except in individuals with systemic conditions that contribute to edema.
Skincare practices including regular skin hygiene using low pH cleansers and moisturizers, use of sunscreen and insect repellant when outdoors and avoidance of injury will help to avoid infection. Antibiotics can be used to treat infections such as cellulitis or as a preventive (prophylactic) measure for recurrent infections (> 3 episodes of cellulitis each year) and athleteโs foot can be treated with antifungal topical medications.
There are currently no available gene therapies or medications approved by the U.S. Food and Drug Administration (FDA) to treat non-syndromic, periphery-dominate primary lymphedema.
Genetic counseling and testing may benefit individuals with primary lymphedema and their families.
Investigations are underway for systemic, injectable and topical medications that may prevent worsening of primary lymphedema by preventing fibrosis and adipose tissue development. Research about how gene variants cause lymphedema may lead to targeted therapy for individuals who have confirmed disease-causing gene variants.
Botanicals such as benzopyrones and saponins (e.g., horse chestnut seed extract) as well as the trace element selenium have been proposed as adjunctive treatments for lymphedema. Benzopyrones, a group of substances such as coumarin, hydroxethylrutin and flavonoid derivatives, may stimulate lymph flow via breakdown of lymph proteins, thereby reducing accumulation and subsequent edema. The effectiveness of such medications for primary lymphedema, however, is under debate and not well-supported in the medical literature. Additionally, liver damage (hepatotoxicity) has been reported in up to 6% of patients taking coumarin, and more research is necessary to determine the long-term effectiveness and safety of benzopyrone therapy in individuals with primary lymphedema.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
International Lymphatic Disease and Lymphedema Patient Registry and Biorepository
TEXTBOOKS
Schaverien MV, Dayan JH. Multimodal Management of Upper and Lower Extremity Lymphedema. Springer International Publishing. 2022.
Cheng MH, Chang DW and Patel KM. Principles and Practice of Lymphedema Surgery, 2nd Edition. Elsevier. 2021.
Liu N. Peripheral Lymphedema: Pathophysiology, Modern Diagnosis and Management. Springer International Publishing. 2021.
Lee BB, Rockson S, Bergan J. Lymphedema: A Concise Compendium of Theory and Practice. Springer International Publishing. 2018.
Zuther JE, Norton S. Lymphedema Management: The Comprehensive Guide for Practitioners, 4th ed. Thieme. 2018.
Greene AK, Slavin SA, Brorson H. Lymphedema. Springer International Publishing. 2015.
JOURNAL ARTICLES
Anand NC, Campbell EH, Baum CL, et al. Association of lower extremity lymphedema and nonmelanoma skin cancers. Mayo Clinic Proceedings. 2023;98(11):1653-1659. doi:10.1016/j.mayocp.2023.02.030
Senger JLB, Kadle RL, Skoracki RJ. Current concepts in the management of primary lymphedema. Medicina. 2023;59(5):894. doi:10.3390/medicina59050894
Lee E, Biko DM, Sherk W, Masch WR, Ladino-Torres M, Agarwal PP. Understanding lymphatic anatomy and abnormalities at imaging. Radiographics. 2022;42(2):487-505. doi:10.1148/rg.210104
Sudduth CL, Greene AK. Primary Lymphedema: Update on genetic basis and management. Adv Wound Care. 2022;11(7):374-381. doi:10.1089/wound.2020.1338
Brouillard P, Witte MH, Erickson RP, et al. Primary lymphoedema. Nature Review Disease Primers. 2021;7(1):1-23. doi:10.1038/s41572-021-00309-7
Gordon K, Mortimer PS, van Zanten M, et al. The St Georgeโs classification algorithm of primary lymphatic anomalies. Lymphatic Research and Biology. 2021;19(1):25-30. doi:10.1089/lrb.2020.0104
Kim PJ, Mufti A, Sachdeva M, et al. Stewart-Treves syndrome and other cutaneous malignancies in the context of chronic lymphedema: a systematic review. International Journal of Dermatology. 2021. doi:10.1111/ijd.15736
Rockson SG. Advances in lymphedema. Circulation Research. 2021;128(12):2003-2016. doi:10.1161/CIRCRESAHA.121.318307
Cheng MH, Liu TTF. Lymphedema microsurgery improved outcomes of pediatric primary extremity lymphedema. Microsurgery. 2020;40(7):766-775. doi:10.1002/micr.30622
Gordon K, Varney R, Keeley V, et al. Update and audit of the St Georgeโs classification algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis. Journal of Medical Genetics. 2020; 57(10): 653โ659. doi.org/10.1136/jmedgenet-2019-106083
Sudduth CL, Maclellan RA, Greene AK. Study of 700 Referrals to a Lymphedema Program. Lymphatic Research and Biology. 2020;18(6):534-538. doi:10.1089/lrb.2019.0086
Greene AK, Goss JA. Diagnosis and staging of lymphedema. Semin Plast Surg. 2018;32(1):12-16. doi:10/ggkqzb
Poage EG, Rodrick JR, Wanchai A, et al. Exploring the usefulness of botanicals as an adjunctive treatment for lymphedema: a systematic search and Review. PM&R. 2015; 7: 296-310.
Lee BB, Andrade M, Antignani PL, et al. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol. 2013;32(6):541-574.
INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lymphatic malformation, 1. Entry No: 153100, Last Edited 11/14/2023. Available at: http://omim.org/entry/153100. Accessed February 7, 2024.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lymphatic malformation, 5. Entry No: 153200, Last Edited 01/10/2019. Available at: http://omim.org/entry/153200. Accessed February 7, 2024.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lymphedema Distichiasis Syndrome. Entry No: 153400, Last Edited 07/13/2023. Available at: https://omim.org/entry/153400. Accessed February 7, 2024.
Schwartz RA. Lymphedema. Medscape. Updated: Updated: April 18, 2023. Lymphedema: Practice Essentials, Background, Pathophysiology (medscape.com). Accessed February 7, 2024.
Sleigh BC, Manna B. Lymphedema. [Updated 2023 Apr 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537239/. Accessed March 10, 2024.
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