Genetics and Primary Lymphedema

Introduction

Protein-rich lymph fluid continually and naturally seeps out of the bloodstream and collects in the body’s tissues at the rate of 1-2 liters per day. The lymphatic system collects this lymph fluid, filters it through the lymph nodes to remove dead cells, bacteria, and toxins, and then returns it to the bloodstream. Muscles pump the lymph fluid through the lymphatic vessels while one-way valves prevent it from back-flowing. Lymphedema is the swelling that occurs when this fluid does not drain properly or adequately from the tissues.

Understanding the Impact of Genetics

Lymphedema is typically classified as either primary or secondary. Primary lymphedema is caused by a lymphatic system that did not develop properly, and although symptoms are often present at birth, it is also not unusual for symptoms to first appear in puberty or even late adulthood. 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% (1 in 2) chance of inheriting the lymphedema-causing gene (mutation) from a parent with primary lymphedema. However, there is “variable expression,” meaning that it could affect one family member’s left foot, another member’s right foot and leg, and yet another family member might have swelling in both feet and/or legs. There is also “incomplete penetrance” in primary lymphedema, meaning 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. 

Secondary lymphedema, the most common cause of lymphedema, results from a lymphatic system that has been damaged or blocked by some environmental cause such as surgery, radiation, injury, or infection. 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

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. 

FOXC2

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. Our article entitled "HGF and MET mutations in primary and secondary lymphedema," was published in 2008 in the scientific journal, Lymphatic Research and Biology.

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, please contact Kara Levine M.S. at (412) 624-4659 or toll free at (800) 263-2152 or send an e-mail to genetics@pitt.edu. More information about the inheritance of primary lymphedema and updates on our research are also available at www.hgen.pitt.edu/projects/lymph.

For more information about Genetic Testing, read Genetic Testing for Primary Lymphedema.

Credits: This article, written by Kara Levine M.S., is reprinted with permission from the Lymphedema Network’s Lighthouse newsletter, January 2010.

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Category: Are You at Risk for Lymphedema? Updated: 2010-02-13