The main symptom associated with hereditary lymphoedema is swelling (oedema) or puffiness in different parts of the body because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the epidermis (lymphoedema). Swelling frequently occurs in one or both legs, but may also be present in the trunk, face, genitalia and arms. When lymphoedema 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 cases, swelling may cause tightness, discomfort and unusual tingling sensations or paraesthesia’s 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” hard texture.

 

Hereditary lymphoedema type IA (Milroy’s disease) is characterized by swelling (oedema) that is present at or shortly after birth (congenital). In rare cases, oedema may develop later in life. The legs are most often affected. The extent and location of oedema varies greatly from case to case even among individuals in the same family. In some cases, the genitals may also be affected. Additional complications sometimes associated with hereditary lymphoedema type I include up-slanted toenails, small warty growths on the affected areas called papillomatosis, abnormally large or prominent leg veins, and, in males, urethral abnormalities and the development of a fluid-filled sac along the spermatic cord of the scrotum (hydrocele).

 

Hereditary lymphoedema type II (Meige disease, lymphoedema praecox) develops around puberty or shortly thereafter in most individuals. This is the most common type of primary lymphoedema. In addition to lymphoedema of the legs, other areas of the body such as the arms, face and larynx may be affected. Some individuals may develop yellow nails.

 

Lymphoedema tarda is defined as primary lymphoedema occurring after the age of 35. The legs are most often affected, but the arms and other areas may be affected as well.

 

Hereditary lymphoedema may progress and, in some cases, may improve over time. Obesity makes management of lymphoedema more difficult. Affected individuals with lymphoedema are at risk for developing infections including bacterial infection of the skin and underlying tissue (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.

 

In rare cases of persistent lymphoedema, additional complications may develop including fluid (e.g., chyle) accumulation body cavities such as the thorax (chylothorax) and abdomen (chylous ascites). Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some people with hereditary lymphoedema, the lymphatic vessels may rupture or become blocked (obstructed), causing chyle to accumulate in the chest cavity (chylothorax). Addition of a mild diuretic has been reported to be a valuable adjunct to dietary control.

 

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. Angiosarcomas 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. This cancerous tumor may rarely develop in longstanding cases of primary or secondary lymphedema. Angiosarcoma occurs in the lymphedematous extremity but can spread to the adjacent trunk and lungs.

 

CAUSES

 

Many researchers believe that hereditary lymphoedema may result from changes or mutations in one of the different disease genes (genetic heterogeneity). Most cases of hereditary lymphoedema type IA and type II are inherited as autosomal dominant traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

 

AFFECTED POPULATIONS

 

Hereditary lymphoedema affects females more often than males. The estimated prevalence of these disorders is 1 in 6,000 individuals within the general population. Hereditary lymphoedema type II (Meige syndrome) is the most common form accounting for approximately 80 percent of cases. The prevalence of hereditary lymphoedema type I (Milroy disease) is unknown.

 

Hereditary lymphoedema may be associated with several genetic multi-system disorders including Noonan syndrome, Klippel-Trénaunay-Weber syndrome, lymphoedema-hypoparathyroid syndrome, and Turner syndrome.

 

Researchers have determined that hereditary lymphoedema type II (Meige syndrome) and three other disorders occur due to different mutations of the same gene (FOXC2). These disorders include yellow nail syndrome, distichiasis-lymphoedema syndrome, and lymphoedema-ptosis syndrome. The exact relationship between these disorders is unknown.

 

Yellow nail syndrome is a rare disorder characterized by yellow, thickened, and curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Yellow nail syndrome is usually associated with the presence of fluid in the lungs (pleural effusion) and swelling of the arms and legs (lymphoedema). Other respiratory problems may occur such as chronic inflammation of the bronchi and bronchioles, chronic bronchitis, and/or ongoing inflammation of the membranes that line the sinus cavities (sinusitis). Lymphoedema usually occurs around puberty. Yellow nail syndrome occurs because of mutations to the FOXC2 gene and is inherited as an autosomal dominant trait.

 

Distichiasis-lymphoedema syndrome is a rare autosomal dominant multi-system disorder characterized by swelling due to fluid accumulation that usually occurs around puberty and the development of extra eyelashes along the posterior border of the lid margins (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects the legs. Additional anomalies associated with this disorder include cleft palate, droopy eyelids (ptosis), abnormalities of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea), cysts on the spinal cord, an abnormal sensitivity to light (photophobia), and cardiac (heart) defects. Distichiasis-lymphoedema syndrome is caused by mutations of the FOXC2 gene and is inherited as an autosomal dominant trait.

 

Lymphoedema-ptosis syndrome is an extremely rare genetic disorder characterized by swelling because of fluid accumulation and droopy eyelids (ptosis). Swelling most often affects the legs. Lymphoedema usually occurs at or shortly after puberty. Lymphoedema-ptosis syndrome occurs because of mutations in the FOXC2 gene and is inherited as an autosomal dominant trait.

 

DIAGNOSIS

 

The diagnosis of hereditary lymphoedema may be confirmed by a thorough clinical evaluation and a variety of specialized imaging tests including lymphoscintigraphy, ultrasound, and magnetic resonance imaging (MRI). During lymphoscintigraphy, a radioactively labeled colloid substance is injected intradermally into either the hands or feet. The time required for the tracer to be transported from the point of injection to the regional lymph nodes is recorded. In congenital lymphoedema, the tracer may move sluggishly or not move from the site of injection. During an ultrasound, reflected sound waves create an image of the developing fetus. An ultrasound is used to rule out other conditions. A Doppler ultrasound can evaluate venous conditions such as varicose veins and venous blood clots. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI is used to detect findings characteristic of hereditary lymphoedema including swelling (oedema), a mass surrounded by a sac containing lymph fluid (lymphocele), and the formation of fibrous tissue (fibrosis).

 

RELATED DISORDERS

 

Symptoms of the following disorders can be similar to those of hereditary lymphoedema. Comparisons may be useful for a differential diagnosis.

 

SECONDARY LYMPHOEDEMA

 

Secondary lymphoedema is an acquired disorder that results from obstruction or damage to the lymphatic system. Affected individuals experience swelling due to the accumulation of lymph in the affected area. Secondary lymphoedema is an acquired condition resulting in damage to or obstruction of previously normal lymphatic vessels and channels. There are many causes and the most common causes are:

 

* Surgery (e.g. the removal of lymph nodes due to cancer-patients are

at lifelong risk)

* Any surgery resulting in damage to lymph vessels and scar tissue

formation (from Orthopaedic, Vascular, Plastic Surgery procedures)

* Radiation of lymph nodes

* Injury/Trauma

* Infection (cellulitis)

* Cancerous tumor infiltration

* Chronic Venous Insufficiency

* Chronic Wounds

* Filariasis (parasitic invasion of lymph nodes and vessels following

a mosquito bite carrying the filariasis worm. This is not common in South Africa, but a person may have contracted it while traveling in areas where the mosquito/parasite is found

 

The most common cause and the highest incidence of secondary lymphoedema worldwide occurs in tropical and subtropical regions and is filarial

infection in which lymphatic obstruction is caused by a parasitic

disease known as lymphatic filariasis. Lymphatic filariasis is caused by

three different species of worms known as Brugia malayi, Brugia timori and Wuchereria bancrofti. These worms cause damage and inflammation to the lymphatic system. The worms are introduced into the human body through the bite of infected mosquitoes. Secondary lymphoedema is treated by addressing the underlying condition. For example, in lymphatic filariasis, certain drugs are used to kill filarial larvae and worms.

 

DIAGNOSING LYMPHOEDEMA

 

As with all medical conditions, correct diagnosis makes correct treatment possible. It is very important to consult with a doctor if swelling develops suddenly. In some cases, the diagnosis and cause are very clear, and no special tests required. However, sometimes special testing is needed. The following are a few of the tests available.

 

LYMPHOSCINTIGRAPHY

 

A radioactive tracer is injected in the web spaces of the toes or fingers and the movement of this radioactive tracer within the lymphatic system is monitored. The flow and emptying of the glands is timed and compared to the unaffected side for comparison.

 

MRI

 

A technique mainly to assess the presence of tumors, but also used to assess vascular infiltration into an area. It is very expensive and rarely used for lymphatic mapping.

 

VENOUS DOPPLER:

 

There are many reasons that swelling can occur. One very serious and potentially life-threatening reason is due to a Deep Vein Thrombosis (DVT). The Doppler Ultrasound is one of the tests used to diagnose a DVT. It is also used to see if one of the causes of the swelling is a vascular problem (ie. the vein or circulation).

 

ICG LYMPHOGRAPHY:

 

This is a new technique, soon to be available in South Africa. A fluorescent tracer is injected into the limb. A near infra-red camera is used to visualize the tracer. The lymphatic vessels and function can be mapped in real time, as well as the location of obstruction or dysfunction and its severity. It is a very detailed and accurate assessment.