NORD gratefully acknowledges 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.
Hereditary lymphedema is a genetic condition affecting the lymphatic system and is characterized by chronic swelling (edema) of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. In hereditary lymphedema, lymphatic fluid collects in the subcutaneous tissues under the outermost layer of skin (epidermis) due to obstruction, malformation or underdevelopment (hypoplasia) of various lymphatic vessels. This leads to swelling (lymphedema) and thickening as well as hardening of the skin in affected areas, most commonly in the legs and feet. Additional symptoms may include tingling, numbness and changes in the nails or skin. The degree of edema is often progressive, though it may improve in the early years in some patients.
Lymphedema may be classified as primary or secondary. Hereditary lymphedema is a primary lymphedema caused by abnormalities in lymph vessels or nodes due to genetic changes (mutations). In contrast, secondary lymphedema is an acquired condition resulting from damage to the lymphatic system from surgery, tumor, radiation therapy, trauma or infection in the absence of any anatomical abnormalities.
There are three forms of hereditary lymphedema which are characterized by age of onset: type I (congenital or up to 2 years of age); type II (from 2 to 35 years of age) and lymphedema tarda (after 35 years of age). Type I is often associated with mutations in the FLT4 gene, while type II and lymphedema tarda have been more recently associated with the FOXC2 gene. In most patients, hereditary lymphedema is inherited in an autosomal dominant manner; however, there is variability in symptoms and severity even within the same family.
The main symptom associated with hereditary 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 legs, swelling is usually most noticeable in the foot and ankle but may also be present in the calf and thigh. In some people, swelling may cause tightness, discomfort and unusual tingling sensations (paresthesias) 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, thickened or scaly skin (hyperkeratosis) resulting in a “woody” texture.
Hereditary lymphedema type I (Milroy disease) is characterized by edema that is present at or shortly after birth (congenital). Ultrasound scanning during pregnancy may indicate if a fetus is affected if swelling of the dorsum of the feet is noted in the second or third trimester. In rare cases, edema may develop later in life. The legs are most often affected, 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. Additional complications sometimes associated with hereditary lymphedema type I include upslanting toenails, small warty growths on the affected areas (papillomatosis), abnormally 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). Bacterial infection of the skin and underlying soft tissues (cellulitis) has also been reported in approximately 20% of individuals, which may increase swelling due to additional damage to lymphatic vessels.
Hereditary lymphedema type II (Meige disease or lymphedema praecox) develops around puberty or shortly thereafter in most individuals. This is the most common type of primary lymphedema. In addition to lymphedema of the legs, other areas of the body such as the arms, face and voice box (larynx) may be affected. Some individuals may develop yellow nails.
Lymphedema tarda is defined as primary lymphedema occurring after the age of 35. Edema primarily occurs in the legs, but the arms and other areas may be affected as well. In women, the lower extremities are most often affected.
In all subtypes of hereditary lymphedema, the degree of edema can progress; in some people, especially in early years, edema may improve over time. Obesity makes management of lymphedema more difficult. Affected individuals with lymphedema are at risk for developing infections including cellulitis or infection of the lymphatic vessels (lymphangitis). These infections are characterized by areas of warm, painful and reddened skin. Red skin “streaks” 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). Cellulitis is more common in males than females. Athlete’s foot (tinea pedis) can cause cracks in the interdigital skin, bacterial invasion and cellulitis. Pregnant individuals with hereditary lymphedema may experience increased swelling during pregnancy.
In rare cases, additional complications can include accumulation of milky fluid consisting of fat droplets and lymph (chyle). Chyle is absorbed during digestion by the lymphatic vessels located around the intestine and drains into the thoracic duct in the upper chest before being deposited into veins, where it mixes with blood. In some individuals with hereditary lymphedema, the lymphatic vessels may rupture or become blocked (obstructed), causing chyle to accumulate in the chest cavity (chylothorax) or abdomen (chylous ascites).
Affected individuals may also be at a greater risk than the general population for developing a malignancy at the affected site. These malignancies include angiosarcoma, which are cancerous tumors that develop from blood or lymphatic vessels. They may occur in any area of the body. A specific type of angiosarcoma is known as lymphangiosarcoma, or Stewart-Treves syndrome. Rarely, this cancerous tumor may develop in long-standing cases of primary or secondary lymphedema. Angiosarcoma occurs in the lymphedematous extremity but can spread to the adjacent trunk and lungs.
Most cases of hereditary lymphedema type I are caused by changes (mutations) in the FMS-like tyrosine kinase 4 (FLT4) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of 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. 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. Some cases of hereditary lymphedema type II and lymphedema tarda have been linked to mutations in the forkhead box C2 (FOXC2) gene, which plays an essential role in regulating lymphatic valve development. Mutations in these genes cause abnormalities in the lymphatic system that do not allow fluid to drain properly, resulting in edema.
Most cases of hereditary lymphedema type I and type II are inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Most individuals diagnosed with hereditary lymphedema type I have an affected parent, though approximately 10% may have the disorder due to a non-inherited (de novo) FLT4 mutation. Approximately 85%-90% of individuals with a FLT4 mutation will develop edema in the lower extremities by 3 years 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).
Hereditary lymphedema affects females more often than males and is one of the most common causes of primary lymphedema. The estimated prevalence of these disorders is 1 in 6,000 – 10,000 individuals in the general population, and it occurs in all ethnic groups. Hereditary lymphedema type II (Meige syndrome) is the most common form accounting for approximately 80 percent of cases. The prevalence of hereditary lymphedema type I (Milroy disease) is unknown. Approximately 200 cases have been reported in the medical literature.
Hereditary lymphedema can be diagnosed thorough clinical evaluation and a variety of specialized imaging tests such as lymphoscintigraphy, ultrasound and magnetic resonance imaging (MRI). 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. In hereditary lymphedema type I, the tracer may move sluggishly or not 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 hereditary lymphedema including edema, a mass surrounded by a sac containing lymph fluid (lymphocele) and the formation of fibrous tissue (fibrosis). Ultrasound scanning during pregnancy may be able to identify an affected fetus if swelling of the top surface of the feet (dorsum) is visible in the second or third trimester.
For hereditary lymphedema type I, 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 mutation in the FLT4 gene or (2) lymphoscintigraphy showing reduced tracer movement. Because lymphedema can also be a part of many other conditions, genetic testing can sometimes distinguish between a diagnosis of hereditary lymphedema and other inherited disorders.
Treatment for hereditary lymphedema focuses on management of symptoms, primarily reducing edema and preventing infection. For lower leg edema, referral to a lymphedema therapist is recommended. Treatment approaches may include fitting compression hosiery and/or bandaging, massage, supportive shoes, and good skin care. Complete decongestive therapy (CDT) is a form of treatment in which specialized manual techniques (manual lymph drainage) is combined with multi-layered compression bandaging, meticulous skin care, exercise, and the use of well-fitted compression garments. Rehabilitation therapy may be necessary in cases where extreme lymphedema impairs daily activities.
Various surgical techniques have been used to treat individuals with hereditary lymphedema, including the joining of small lymphatic vessels to nearby small veins (microsurgical anastomosis) with the goal of creating new pathways to “rechannel” lymphatic fluid flow into the venous system and thereby reduce swelling. However, this surgery is not generally recommended as limited effectiveness has been reported in the medical literature. Surgery to remove excess fibrous tissue (reducing operation) for cases of severe lymphedema is also available but continued use of compression garments is still necessary. Removal of fat from under the skin (liposuction) has not been found to be effective in primary lymphedema.
To prevent progression of edema or infection, individuals with hereditary lymphedema should 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 decrease fluid retention. Special care should be taken to avoid wounds in any affected area due to reduced resistance to infection. Certain medications such as calcium channel blocking drugs and non-steroidal anti-inflammatory drugs (NSAIDs) may worsen edema in the legs and the benefits and risks of using these medications should be thoroughly discussed with the patient’s physician.
Antibiotics can be used to treat infections such as cellulitis or as a preventive (prophylactic) measure for recurrent infections and athlete’s foot can be treated with antifungal topical medications. Individuals with primary chylous ascites complications should follow a no-fat diet supplemented with medium chain triglycerides and vitamins. Addition of a diuretic such as spironolactone has been reported to be a valuable adjunct to dietary control.
There are currently no available gene therapies or medications approved by the U.S. Food and Drug Administration (FDA) to treat hereditary lymphedema.
Genetic counseling and testing may benefit individuals with hereditary lymphedema and their families.
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 hereditary lymphedema. Benzopyrones, a group of substances such as coumarin, hydroxethylrutin and flavinoid derivatives, may stimulate lymph flow via breakdown of lymph proteins, thereby reducing accumulation and subsequent edema. The effectiveness of such medications, 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 hereditary lymphedema.
Occasionally, drugs that promote fluid mobilization (diuretics) have been suggested in the treatment of lymphedema. These medications increase urinary output and may help to reduce swelling in some affected individuals; however, diuretics have not been proven successful in reducing the swelling in primary lymphedema but may be beneficial in patients with mixed origin edema (e.g., phlebolymphedema). The prolonged use of diuretics for the treatment of hereditary lymphedema should be carefully directed by a physician as these medications may have several long-term side effects.
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