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Genetics and Primary Lymphedema


Protein-rich lymph fluid continually, and naturally, seeps out of the bloodstream and collects in the body’s tissues at the rate of 1 to 2 liters per day.

The lymphatic system collects this lymph fluid and filters it through the lymph nodes to remove dead cells, bacteria, and toxins. 

The filtered fluid returns to the bloodstream. "Muscles pumps" and "joint pumps" through out the body cause this lymph fluid to move through the lymphatic vessels which contain one-way valves to prevent it from flowing back from the heart. Lymphedema is the swelling that occurs when this fluid does not drain properly, or adequately, from the tissues.


  • PRIMARY LYMPHEDEMA (PLE) is an inherited condition that is due to a lymphatic system that does not develop properly before birth. The symptoms of PLE are not always present at birth. In some cases, these symptoms  do not appear until puberty. At other times this does not occur until late adulthood.
  • SECONDARY LYMPHEDEMA (SLE) is the most common form of lymphedema. This condition is caused by damage, blockage, or other environmental factors such as surgery, radiation, injury, or infection.


  • Primary lymphedema is usually inherited as an autosomal dominant disease with incomplete penetrance and variable expression. “Autosomal dominant” means that both males and females have a 50/50 or one in two chance of inheriting the mutated (changed) lymphedema-causing gene from a parent with primary lymphedema.
  • However, there is a “variable expression,” meaning that it could affect one family member’s left foot, while another family member’s right foot and leg can have another family member might have swelling in both feet and/or legs. There is also “incomplete penetrance” in primary lymphedema. This means that some family members might inherit the mutation and have no signs of swelling at all. This incomplete penetrance might appear as a “skipped generation” in some families. 
  •  Although the initiating circumstances surrounding the onset of primary and secondary lymphedema are different, knowledge of the genetic mechanisms that cause primary lymphedema will lead to a better understanding of the function of the lymphatics, new ideas for treatment of both primary and secondary lymphedema, and possibly even the identification of genetic risk factors that increase an individual’s susceptibility for secondary lymphedema.
  • Therapeutic implications of increased knowledge about the genetics of the lymphatic system include the potential for drugs that modify the activity of cell receptors and growth factors involved in maintaining a healthy lymphatic system.
  • Because of the complexity of the lymphatic system, it is widely accepted that there are many genes involved in its development. Changes (mutations) in any one of these genes could theoretically cause primary lymphedema. “Genetic heterogeneity” is the term used to describe this phenomenon in which different genes can cause the same or a similar condition. Although different genes may cause lymphedema in different families, only one of these genes is typically responsible for the lymphedema in any particular family.


The Lymphedema Family Study has used a combination of linkage analysis and candidate gene screening to identify several causative genes for lymphedema. “Linkage analysis,” or “linkage studies,” is a method in which the genetic material (DNA) is compared between family members with and without lymphedema.

Differences between these two groups within a family can help pinpoint the chromosomal location of the gene causing lymphedema in that particular family. The larger the family, the more information that family provides about the location of a gene. Because there are many genes that can cause lymphedema, different families can help point researchers toward different genes.

By using this method of linkage analysis, the Lymphedema Family Study was able to determine the location of the first lymphedema gene on chromosome 5 in some families with congenital lymphedema (Milroy’s Disease). Once the chromosomal location was identified, a gene in this vicinity known to be involved in lymphatic development, vascular endothelial growth factor receptor 3 or VEGFR-3 (previously referred to as FLT4), was sequenced in family members with lymphedema. Through this positional candidate gene screening, variation within this gene was found in several participating families. Further studies were performed, and it was determined that these variations were, in fact, disease-causing (causative) mutations.


VEGFR-3 belongs to a family of growth factors and growth factor receptors which are known to be involved in the formation of lymphatic vessels during fetal development. We have observed causative mutations in the VEGFR-3 gene in several participating families. These mutations prevent this receptor from responding to the messages it receives from certain growth factors that signal development of lymphatic vessels; this results in an underdevelopment (hypoplasia) of these vessels. We have identified changes or mutations in the VEGFR-3 gene in approximately 5% of the families participating in the Lymphedema Family Study. 


The FOXC2 Gene
(Courtesy of Gentics Home Reference)

 FOXC2 was the second lymphedema gene found, and was first identified in 2000 by Fang et al. FOXC2 is responsible for causing the lymphedema-distichiasis syndrome (LD). Individuals with LD have lymphedema of pubertal or adult onset as well as distichiasis, which is the presence of extra eyelashes. These eyelashes may simply appear long and thick, or they may become ingrown and irritate the eye, in which case they are often removed. Less frequently, individuals with LD may be born with a heart defect, cleft palate (opening in the roof of the mouth), or ptosis (droopy eyelids). We have identified changes or mutations in the FOXC2 gene in approximately 7% of the families participating in the Lymphedema Family Study.

In 2008, through candidate gene screening, the Lymphedema Family Study identified 2 additional lymphedema genes, called hepatocyte growth factor (HGF) and its receptor MET, both of which are located on chromosome 7. The HGF/MET biologic pathway is also thought to play a role in the growth and development of lymphatic vessels. Collectively these two genes account for approximately 4% of the families participating in the Lymphedema Family Study and in one patient with secondary lymphedema.

Not all hereditary lymphedema is caused by VEGFR3, FOXC2, or HGF/MET, indicating that there is at least one other gene (probably many more) responsible for hereditary lymphedema. The Lymphedema Family Study continues to search for the locations of these additional lymphedema genes. The identification of these other lymphedema genes will be dependent on finding more families with primary lymphedema. Therefore, advances in understanding the underlying causes of lymphedema are critically dependent on the voluntary participation of individuals and families in this research. We are continuing to recruit families in which at least one individual is affected with primary lymphedema.

An Offer of Help

If you have questions, or if you and your family are interested in participating, pleast contact Kara Levine, M.D, (toll free) at 800-263-2152 or by e-mail at genetics@pitt.edu .

More information about the inheritance of primary lymphedema and updates on our research at out website www.hgen.pitt.edu/projects/lymph.

Genetic Testing information is available by reading the article Genetic Testing for Primary Lymphedema.

Credits: This article was written by Kara Levine M.S., who is a member of the University of Pittsburgh Lymphedema study staff toward the goal of explaining how genetic mutations can cause some difficulties. It is reprinted here with permission from the Lymphedema Network’s Lighthouse newsletter, January 2010 Atlanta, GA. 

NOTE: This article was reviewed in 2014 and the content is still valid.

Got a question or comment? Post in the 'Are You at Risk for Lymphedema?' forum.
Category: Are You at Risk for Lymphedema? Updated: 2014-05-26


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