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HEREDITARY PRIMARY LYMPHEDEMA 

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Lymphedema, Hereditary

Lymphedema

Synonyms

None

Disorder Subdivisions

Hereditary Lymphedema, Type I
Congenital Hereditary Lymphedema
Milroy Disease
Nonne-Milroy-Meige Syndrome
Hereditary Lymphedema, Type II
Meige's Lymphedema
Familial Lymphedema Praecox
Hereditary Lymphedema Tarda

Related Disorders List

Information on the following diseases can be found in the Related Disorders section of this report:

Hereditary Angioedema
Lymphedema (Traumatic)
Lymphatic Filariasis
Distichiasis-Lymphedema Syndrome
Lymphedema and Ptosis

General Discussion

Hereditary Lymphedema is an inherited disorder of the lymphatic system that is characterized by abnormal swelling of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain fluid (lymph) and blood cells throughout the body. Lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to the obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels.

There are three forms of Hereditary Lymphedema: Congenital Hereditary Lymphedema or Milroy Disease, Lymphedema Praecox or Meige Disease, and Lymphedema Tarda. In most cases, Hereditary Lymphedema is inherited as an autosomal dominant genetic trait.

Symptoms

The primary symptom of Hereditary Lymphedema is swelling or puffiness in different parts of the body due to the accumulation of lymphatic fluid in the soft layers of tissue under the skin (lymphedema). Swelling frequently occurs below the waist, especially in the legs, but may also be present in the face, voice box (larynx), neck and arms. When lymphedema develops in the legs, swelling may begin in the foot and move upward. In some cases, swelling may cause discomfort and unusual tingling sensations (paresthesias) in the affected areas. Poor healing, following even minor trauma (e.g., cut or insect bite), may also occur; permanent structural changes in the skin, with abnormal thickening (fibrosis), often follow longstanding edema.

Infants with Hereditary Lymphedema Type I, also known as Congenital Hereditary Lymphedema or Milroy Disease, have areas of swelling at birth. The swelling tends to slowly worsen with advancing age.


Hereditary Lymphedema Type II or Meige Disease usually develops during childhood, adolescence, or early adulthood. This form of the disease usually produces severe swelling in areas below the waist. The first symptoms of Hereditary Lymphedema Type II usually include red skin over areas of swelling and associated discomfort and/or inflammation.

Hereditary Lymphedema Tarda usually occurs after the age of 35 years. The symptoms are similar to those of Hereditary Lymphedema Type II.

Complications of Hereditary Lymphedema may include inflammation of lymphatic vessels (lymphangitis) and infection of the skin (cellulitis) characterized by areas of warm and painful reddened skin that are hot to the touch. Red skin "streaks" may also develop. A general feeling of ill health (malaise), fever, chills, and/or headaches may also occur. If left untreated, cellulitis can lead to skin abscesses, areas of ulceration, and/or tissue damage (necrosis). Some people with this condition may develop persistent fluid accumulation in the lungs (pleural effusion). The most serious long-term complication of all forms of Hereditary Lymphedema is a minor increased risk for the development of a malignancy in the affected area (i.e., lymphangiosarcoma).


Causes

Most cases of Hereditary Lymphedema are inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

In some rare cases, Hereditary Lymphedema is thought to be inherited as an autosomal recessive or X-linked recessive genetic disorder.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons.

Some cases of Hereditary Lymphedema may occur because of a spontaneous change in genetic material early in fetal development (sporadic).

The symptoms of Hereditary Lymphedema develop because of obstruction of the lymphatic vessels due to multiple malformations of the lymphatic vascular system. In some cases, there may be a reduction in the number of lymphatic vessels or the vessels may be underdeveloped (hypoplastic). However, in some cases, the reverse is true and lymphatic vessels may be unusually large (hyperplastic) and numerous.

Affected Populations

Congenital Hereditary Lymphedema (Type I) affects more females than males. Hereditary Lymphedema Type II (Meige Disease) affects males and females in equal numbers.

Approximately 1 in 6,000 people in the United States are affected by Hereditary Lymphedema. The symptoms of Congenital Hereditary Lymphedema (Type I) are typically present at birth. The onset of Hereditary Lymphedema Type II can occur during childhood, adolescence, or adulthood (i.e., between the ages of 10 to 35 years). The symptoms of Hereditary Lymphedema Tarda generally occur after the age of 35 years.


Related Disorders

Symptoms of the following disorders can be similar to those of Hereditary Lymphedema. Comparisons may be useful for a differential diagnosis:


Hereditary Angioedema is a rare inherited vascular disorder characterized by the excessive accumulation of body fluids in lymphatic vessels or veins. The outstanding symptom of this disorder is swelling (edema) on the back of the hands or feet, eyelids, lips, and/or genitals. Edema may also occur in the mucous membranes that line the respiratory and digestive tracts. The areas of swelling may be hard and painful, but they are typically not red or itchy (pruritic). A skin rash (urticaria) is rarely present. Hereditary Angioedema is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Angioedema" as your search term in the Rare Disease Database.)

Traumatic Lymphedema is caused by injury to the lymph system or blunt trauma (bruising). Localized lymphedema may be due to postinfectious syndromes, post-radiation fibrosis, tumor growth, and/or surgery (e.g., mastectomy). Symptoms may include swelling, pitting, redness, discomfort, and/or tingling sensations.


Elephantiasis is an infectious tropical disease of the lymphatic system and is characterized by gross enlargement of an arm or leg or other areas of the trunk or head. The skin develops a thickened, pebbly appearance and may become ulcerated and darkened. Fever, chills, and a general feeling of ill health (malaise) may also be present. Inflammation of the lymphatic vessels causes extreme enlargement of the affected areas. This condition occurs most commonly in tropical regions and particularly in parts of Africa. (For more information on this disorder, choose "Elephantiasis" as your search term in the Rare Disease Database.)

The following disorders may occur in association with Hereditary Lymphedema as secondary characteristics. They are not necessary for a differential diagnosis:

Y
ellow Nail Syndrome is a rare disorder characterized by yellow, thickened, and curved nails with almost complete stoppage of nail growth. A loss of cuticles may also be associated with this syndrome. Loosening of the nails (onycholysis) may cause loss of some nails. This condition is usually associated with the presence of fluid in the lungs (plural effusion) and swelling of the arms and legs (lymphedema). Other respiratory problems may occur such as chronic inflammation of the bronchi and bronchioles (bronchiectasis), chronic bronchitis, and/or ongoing inflammation of the membranes that line the sinus cavities (sinusitis). The exact cause of this disease is not known. (For more information on this disorder, choose "Yellow Nail" as your search term in the Rare Disease Database.)

D
istichiasis-Lymphedema Syndrome is a rare inherited disorder characterized by the presence of extra eyelashes (distichiasis) and swelling of the arms and legs (lymphedema). Swelling of the legs, especially below the knees, and eye irritation are common in people with this disorder. Occasionally, cysts on the spine (epidural) and other abnormalities of the spinal column may also occur. Distichiasis-Lymphedema Syndrome is inherited as an autosomal dominant genetic trait.

Lymphedema and Ptosis is an extremely rare inherited condition and is characterized by droopy eyelids (ptosis) and swelling (lymphedema), especially in the legs.

Standard Therapies

Diagnosis

The diagnosis of Hereditary Lymphedema may be confirmed by a thorough clinical evaluation and specialized imaging tests. The structure of the lymphatic system may be investigated with special nuclear studies (i.e., indirect radio isotope, lymphoscintigraphy, magnetic resonance imaging (MRI) or CT scanning may yield information that supports the diagnosis.


T
reatment

Complete decongestive therapy (CDT) is a form of treatment in which specialized massage techniques are coupled with therapeutic bandaging, meticulous skin care, exercise, and the use of well-fitted compression garments.

Occasionally, drugs that promote excessive urinary output (i.e., diuretics) may be somewhat helpful for people with Hereditary Lymphedema. These medications increase urinary output and may help to reduce swelling in some affected individuals. However, diuretics have not been uniformly successful in reducing the swelling associated with this disorder. 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.


In some cases, the surgical joining of small lymphatic vessels to nearby small veins (microsurgical anastomosis) has had some limited success in people with Lymphedema. The goal of this surgery is to reduce swelling by creating new pathways for lymphatic fluid flow and "rechanneling" this flow into the venous system.

Genetic counseling will benefit people with Hereditary Lymphedema and their families.

Investigational Therapies

Research on genetic disorders and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic and familial disorders in the future.

*Link no longer available*

References

ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). Victor A. McKusick, Editor; Johns Hopkins University, last edit date 4/18/95. Entry Number 153200; last edit date 3/9/99, Entry Number 153100; last edit date 11/6/94, Entry Number 153000.

CECIL TEXTBOOK OF MEDICINE, 20th Ed.: J. Claude Bennett and Fred Plum, Editors; W.B. Saunders Co., 1996. P. 357.

HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 14th Ed.: Kurt J. Isselbacher, M.D. et al., Editors; McGraw-Hill, Inc., 1998. Pp. 1405-06.

THE MERCK MANUAL, 17th Ed.: Robert Berkow and Mark Beers, Editors; Merck Research Laboratories; 1999. P. 1798.

TEXTBOOK OF DERMATOLOGY, 5th Ed.: R.H. Champion et al., Editors; Blackwell Scientific Publications, 1992. Pp. 2018-23.

BIRTH DEFECTS ENCYCLOPEDIA, Mary Louise Buyse, Editor-In-Chief; Blackwell Scientific Publications, 1990. Pp. 1087-89.

NELSON TEXTBOOK OF PEDIATRICS, 15th Ed.: Richard E. Behrman, Editor; W.B. Saunders Company, 1996. Pp. 1440-41.

DICTIONARY OF MEDICAL SYNDROMES, 3rd Ed.: Sergio I. Magalini, Sabina C. Magalini, and Giovanni de Francisci, Editors; J.B. Lippincott Company, 1990. Pp. 637-38.

18 STEPS TO PREVENTION FOR LOWER EXTREMITIES. S. Thiadens, R.N.; National Lymphadema Network Special Circular (1998).

CDP TREATMENT OF SMALL CHILDREN AND INFANTS WITH PRIMARY (CONGENITAL) LYMPHEDEMA. G. Klose; National Lymphedema Network Newsletter (Jan-Mar 1998; 10(1)). Pp. 1-5.

TREATMENT OF LYMPHEDEMA WITH COMPLETE DECONGESTIVE PHYSIOTHERAPY. J.E. Zuther; National Lymphedema Network Newsletter (Apr-Jun 1999; 11(2)). Pp. 3-8.

PRIMARY LYMPHEDEMA. S.G. Rockson, Author; In: Currenty Therapy in Vascular Surgery, 4th Ed.: C. B. Ernst et al., Editors; Mosby.

LYMPHEDEMA: A REVIEW OF THE RELEVANT ANATOMY AND PHYSIOLOGY OF THE LYMPHATICS. A. Szuba et al.; Vascular Medicine (1997; 2). Pp. 321-26.

LYMPHEDEMA: A REVIEW OF DIAGNOSTIC TECHNIQUES AND THERAPEUTIC OPTIONS. A. Szuba et al.; Vascular Medicine (1998; 3). Pp. 145-56.

HEREDITARY LATE-ONSET LYMPHEDEMA WITH PLEURAL EFFUSION AND LARYNGEAL EDEMA. F.A. Herbert et al.; Arch Intern Med (May 1983; 143(5)). Pp. 913-15.

HEREDITARY LYMPHEDEMA AND DISTICHIASIS. T. Kolin et al.; Arch Ophthalmol (Jul 1991; 109(7)). Pp. 980-81.

LYMPHANGIOSARCOMA IN CHRONIC HEREDITARY OEDEMA (MILROY'S DISEASE). L.A. Brostrom et al.; Ann Chir Gynaecol (1989; 78(4)). Pp. 320-23.

CONGENITAL HEREDITARY LYMPHEDEMA (NONNE/MILROY). D.D. Farhud et al.; Padiatrpa Padol (1989; 24(4)). Pp. 305-07.

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THE LYMPH SYSTEM

The diagram to the below shows the lymphatic system and related organs. (Cancer Research UK)


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HERE IS AN EXCELLANT ARTICLE FROM THE NATIONAL CANCER INSTITUTE INFORMATION FROM PDQCancerMail from the National Cancer Institute Information from PDQ for Patients

Lymphedema

** INTRODUCTION ** This patient summary is adapted from the summary on lymphedema written by cancer experts for health professionals. This and other credible information about cancer treatment, screening, prevention, supportive care, and ongoing trials, is available from the National Cancer Institute. Lymphedema is the buildup of lymph (a fluid that helps fight infection and disease) in the fatty tissues just under the skin. The buildup of lymph causes swelling in specific areas of the body, usually an arm or leg, with an abnormally high amount of tissue proteins, chronic inflammation, and thickening and scarring of tissue under the skin. Lymphedema is a common complication of cancer and cancer treatment and can result in long-term physical, psychological, and social issues for patients.

**OVERVIEW ** The lymphatic system consists of a network of specialized lymphatic vessels and various tissues and organs throughout the body that contain lymphocytes (white blood cells) and other cells that help the body fight infection and disease. The lymphatic vessels are similar to veins but have thinner walls. Some of these vessels are very close to the skin surface and can be found near veins; others are just under the skin and in the deeper fatty tissues near the muscles and can be found near arteries. Muscles and valves within the walls of the lymphatic vessels near the skin surface help pick up fluid and proteins from tissues throughout the body and move the lymph in one direction, toward the heart. Lymph is slowly moved through larger and larger lymphatic vessels and passes through small bean-shaped structures called lymph nodes. Lymph nodes filter substances that can be harmful to the body and contain lymphocytes and other cells that activate the immune system to fight disease. Eventually, lymph flows into one of two large ducts in the neck region. The right lymphatic duct collects lymph from the right arm and the right side of the head and chest and empties into the large vein under the right collar bone. The left lymphatic duct or thoracic duct collects lymph from both legs, the left arm and the left side of the head and chest and empties into the large vein under the left collar bone. The lymphatic system collects excess fluid and proteins from the body tissues and carries them back to the bloodstream. Proteins and substances too big to move through the walls of veins can be picked up by the lymphatic vessels because they have thinner walls. Edema may occur when there is an increase in the amount of fluid, proteins, and other substances in the body tissues because of problems in the blood capillaries and veins or a blockage in the lymphatic system.

Lymphedema may be either primary or secondary

Primary lymphedema is a rare inherited condition in which lymph nodes and lymph vessels are absent or abnormal. Secondary lymphedema can be caused by a blockage or cut in the lymphatic system, usually the lymph nodes in the groin area and the arm pit. Blockages may be caused by infection, cancer, or scar tissue from radiation therapy or surgical removal of lymph nodes. This summary discusses secondary lymphedema.

Acute versus gradual-onset lymphedema

There are four types of acute lymphedema. The first type of acute lymphedema is mild and lasts only a short time, occurring within a few days after surgery to remove the lymph nodes or injury to the lymphatic vessels or veins just under the collar bone. The affected limb may be warm and slightly red, but is usually not painful and gets better within a week after keeping the affected arm or leg supported in a raised position and by contracting the muscles in the affected limb (for example, making a fist and releasing it). The second type of acute lymphedema occurs 6 to 8 weeks after surgery or during a course of radiation therapy. This type may be caused by inflammation of either lymphatic vessels or veins. The affected limb is tender, warm or hot, and red and is treated by keeping the limb supported in a raised position and taking anti-inflammatory drugs. The third type of acute lymphedema occurs after an insect bite, minor injury, or burn that causes an infection of the skin and the lymphatic vessels near the skin surface. It may occur on an arm or leg that is chronically swollen. The affected area is red, very tender, and hot and is treated by supporting the affected arm or leg in a raised position and taking antibiotics. Use of a compression pump or wrapping the affected area with elastic bandages should not be done during the early stages of infection. Mild redness may continue after the infection. The fourth and most common type of acute lymphedema develops very slowly and may become noticeable 18 to 24 months after surgery or not until many years after cancer treatment. The patient may experience discomfort of the skin or aching in the neck and shoulders or spine and hips caused by stretching of the soft tissues, overuse of muscles, or posture changes caused by increased weight of the arm or leg.

Temporary versus chronic lymphedema

Temporary lymphedema is a condition that lasts less than 6 months. The skin indents when pressed and stays indented, but there is no hardening of the skin. A patient may be more likely to develop lymphedema if he or she has: - surgical drains that leak protein into the surgical site - inflammation - an inability to move the limb(s) - temporary loss of lymphatic function - blockage of a vein by a blood clot or inflammation of a vein.

Chronic (long-term) lymphedema

is the most difficult of all types of edema to treat. the damaged lymphatic system of the affected area is not able to keep up with the increased need for fluid drainage from the body tissues. This may happen: - after a tumor recurs or spreads to the lymph nodes - after an infection and/or injury of the lymphatic vessels - after periods of not being able to move the limbs - after radiation therapy or surgery - when early signs of lymphedema have not been able to be controlled - when a vein is blocked by a blood clot. A patient who is in the early stages of developing lymphedema will have swelling that indents with pressure and stays indented but remains soft. The swelling may easily improve by supporting the arm or leg in a raised position, gently exercising, and wearing elastic support garments. Continued problems with the lymphatic system cause the lymphatic vessels to expand and lymph flows back into the body tissues, making the condition worse. This causes pain, heat, redness, and swelling as the body tries to get rid of the extra fluid. The skin becomes hard and stiff and no longer improves with raised support of the arm or leg, gentle exercise, or elastic support garments. Patients with chronic lymphedema are at increased risk of infection. No effective treatment is yet available for patients who have advanced chronic lymphedema. Once the body tissues have been repeatedly stretched, lymphedema may recur more easily.

Risk factors

Factors that can lead to the development of lymphedema include radiation therapy to an area where the lymph nodes were surgically removed, problems after surgery that cause inflammation of the arm or leg, the number of lymph nodes removed in surgery, and being elderly.

Patients who are at risk for lymphedema are those with: - Breast cancer if they have received radiation therapy or had lymph nodes removed. Radiation therapy to the underarm area after surgical removal of the lymph nodes and the number of lymph nodes removed increases the risk of lymphedema. - Surgical removal of lymph nodes in the underarm, groin, or pelvic regions. - Radiation therapy to the underarm, groin, pelvic, or neck regions. - Scar tissue in the lymphatic ducts or veins, under the collar bones, caused by surgery or radiation therapy. - Cancer that has spread to the lymph nodes in the neck, chest, underarm, pelvis, or abdomen. - Tumors growing in the pelvis or abdomen that involve or put pressure on the lymphatic vessels and/or the large lymphatic duct in the chest and block lymph drainage. - An inadequate diet or those who are overweight. These conditions may delay recovery and increase the risk for lymphedema.
Diagnosis

Specific criteria for diagnosing lymphedema do not yet exist. About half of patients with mild edema describe their affected arm or leg as feeling heavier or fuller than usual. To evaluate a patient for lymphedema, a medical history and physical examination of the patient should be completed. The medical history should include any past surgeries, problems after surgery, and the time between surgery and the onset of symptoms of edema. Any changes in the edema should be determined as well as any history of injury or infection. Knowing the medications a patient is taking is also important for diagnosis.

Prevention

Patients at risk for lymphedema should be identified early, monitored, and taught self-care. A patient may be more likely to develop lymphedema if he or she eats an inadequate diet, is overweight, is inactive, or has other medical problems. To detect the condition early, the following should be examined: - comparison of actual weight to ideal weight - measurements of the arms and legs - protein levels in the blood - ability to perform activities of daily living - history of edema, previous radiation therapy, or surgery - other medical illnesses, such as diabetes, high blood pressure, kidney disease, heart disease, or phlebitis (inflammation of the veins). It is important that the patient know about his or her disease and the risk of developing lymphedema. Poor drainage of the lymphatic system due to surgery to remove the lymph nodes or radiation therapy may make the affected arm or leg more susceptible to serious infection. Even a small infection may lead to serious lymphedema. Patients should be taught about arm, leg, and skin care after surgery and/or radiation (see Table 1 below). It is important that patients take precautions to prevent injury and infection in the affected arm or leg, since lymphedema can occur 30 or more years after surgery. Breast cancer patients who follow instructions about skin care and proper exercise after mastectomy are less likely to experience lymphedema. Lymphatic drainage is improved during exercise, therefore exercise is important in preventing lymphedema. Breast cancer patients should do hand and arm exercises as instructed after mastectomy. Patients who have surgery that affects pelvic lymph node drainage should do leg and foot exercises as instructed. The doctor decides how soon patients should start exercising after surgery. Physiatrists (doctors who specialize in physical medicine and rehabilitation) or physical therapists should develop an individualized exercise program for the patient.
 

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LYMPHEDEMA, HEREDITARY, I

Alternative titles; symbols

NONNE-MILROY LYMPHEDEMA
LYMPHEDEMA, EARLY-ONSET
PRIMARY CONGENITAL LYMPHEDEMA; PCLGene map locus 5q35.3

TEXT

A number sign (#) is used with this entry because hereditary lymphedema type I is caused by mutation in the FLT4 gene (136352), which encodes the vascular endothelial growth factor receptor-3.

See hereditary lymphedema type II, also known as Meige lymphedema (153200), and the lymphedema-distichiasis syndrome (153400) for disorders with related phenotypes.

CLINICAL FEATURES

Milroy (1928), a physician in Omaha, Nebraska, described the disorder in a family in which many of the affected persons were prominent in public and professional life. Rosen et al. (1962) observed congenital chylous ascites in an affected infant whose father had recurrent swelling of the scrotum beginning at the age of 20 years. Marked loss of albumin into the intestinal tract with consequent hypoproteinemia was demonstrated. In 2 patients, Hurwitz and Pinals (1964) observed persistent bilateral pleural effusion in which the protein content of the pleural fluid was high. Esterly (1965) described a family with 15 affected members of 3 generations. One child had striking congenital edema of the hands as a main feature and a second had similar swelling of the hands, as well as bilateral involvement of the legs and feet. A sib of the proposita had no apparent lymphedema, although 2 of his 4 children had bilateral swelling of the legs and feet. He was regarded at first as a 'skipped' generation similar to those noted in previous pedigrees of Milroy disease. Closer examination, however, demonstrated a definite 3 x 5 cm area of slight edema on the medial aspect of the left lower leg. This area was warm to the touch and could be pitted against the underlying tibia. High blood flow in the leg affected by congenital lymphedema has been thought to be due to accumulation of vasodilatory metabolites. Lymphedematous legs generally feel warm and the patients have warm feet. The proposita in the family reported by Esterly (1965) could recover the newspaper from her front walk in her bare feet in winter without discomfort. Esterly (1965) reviewed 22 previously documented pedigrees which, with his own family, gave a total of 152 affected persons. 30 MEDLINE Neighbors

Ferrell et al. (1998) studied 13 lymphedema families from the U.S. and Canada. All members of these families were of western European ancestry. In the 13 families, 105 individuals were classified as affected, with a male:female ratio of 1:2.3. The age of onset of lymphedema ranged from prenatal (diagnosed by ultrasound) to age 55 years. When affected x normal matings were analyzed, 76 of 191 children were affected, yielding a penetrance of 80%. 30 MEDLINE Neighbors

INHERITANCE

Holberg et al. (2001) performed a complex segregation analysis and a genomewide search for linkage in 6 previously described families with Milroy congenital lymphedema. Results confirmed that Milroy lymphedema is generally inherited as a dominant condition, but this mode of inheritance did not account for all observed familial correlations. The authors suggested that shared environmental or additional genetic factors may also be important in explaining the observed familial aggregation. 30 MEDLINE Neighbors

MAPPING

In linkage studies of 3 multigeneration families demonstrating hereditary lymphedema segregating as an autosomal dominant with incomplete penetrance, Ferrell et al. (1998) demonstrated a 2-point lod score of 6.1 at theta = 0.0 for marker D5S1354 and a maximum multipoint lod score of 8.8 at marker D5S1354 located at 5q34-q35. Linkage analysis in 2 additional families using markers from the linked region showed 1 family consistent with linkage to distal chromosome 5; in the second family, linkage to 5q was excluded for all markers in the region. 30 MEDLINE Neighbors

Evans et al. (1999) carried out a genomewide search in a 4-generation North American family with what they termed 'dominantly inherited primary congenital lymphedema.' They established linkage to markers from the 5q35.3 region in this family and in 4 additional British families. The locus appeared to be situated in the most telomeric region of 5q35.3. No recombination was observed with D5S408 (lod = 10.03) and D5S2006 (lod = 8.46), with a combined multipoint score of 16.55. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of 0.84 for this disorder. 30 MEDLINE Neighbors

MOLECULAR GENETICS

In a family with hereditary lymphedema, Ferrell et al. (1998) identified a mutation in the FLT4 gene (136352.0001). In several families with autosomal dominant hereditary lymphedema, Karkkainen et al. (2000) identified different mutations in the FLT4 gene (see, e.g., 136352.0002).

ANIMAL MODEL

Congenital lymphedema is autosomal dominant in the pig (9,10:Van der Putte, 1978, 1978).

REFERENCES

1. Esterly, J. R. :
Congenital hereditary lymphoedema. J. Med. Genet. 2: 93-98, 1965.
2. Evans, A. L.; Brice, G.; Sotirova, V.; Mortimer, P.; Beninson, J.; Burnand, K.; Rosbotham, J.; Child, A.; Sarfarazi, M. :
Mapping of primary congenital lymphedema to the 5q35.3 region. Am. J. Hum. Genet. 64: 547-555, 1999.
PubMed ID : 9973292
3. Ferrell, R. E.; Levinson, K. L.; Esman, J. H.; Kimak, M. A.; Lawrence, E. C.; Barmada, M. M.; Finegold, D. N. :
Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum. Molec. Genet. 7: 2073-2078, 1998.
PubMed ID : 9817924
4. Holberg, C. J.; Erickson, R. P.; Bernas, M. J.; Witte, M. H.; Fultz, K. E.; Andrade, M.; Witte, C. L. :
Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families. Am. J. Med. Genet. 98: 303-312, 2001.
PubMed ID : 11170072
5. Hurwitz, P. A.; Pinals, D. J. :
Pleural effusion in chronic hereditary lymphedema (Nonne, Milroy, Meige's disease): report of two cases. Radiology 82: 246-248, 1964.
PubMed ID : 14115303
6. Karkkainen, M. J.; Ferrell, R. E.; Lawrence, E. C.; Kimak, M. A.; Levinson, K. L.; McTigue, M. A.; Alitalo, K.; Finegold, D. N. :
Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nature Genet. 25: 153-159, 2000.
PubMed ID : 10835628
7. Milroy, W. F. :
Chronic hereditary edema: Milroy's disease. J.A.M.A. 91: 1172-1175, 1928.
8. Rosen, F. S.; Smith, D. H.; Earle, R., Jr.; Janeway, C. A.; Gitlin, D. :
The etiology of hypoproteinemia in a patient with congenital chylous ascites. Pediatrics 30: 696-706, 1962.
9. Van der Putte, S. C. J. :
Congenital hereditary lymphedema in the pig. Lymphology 11: 1-9, 1978.
PubMed ID : 642582
10. Van der Putte, S. C. J. :
The pathogenesis of congenital hereditary lymphedema in the pig. Lymphology 11: 10-21, 1978.
PubMed ID : 642583

CONTRIBUTORS

Cassandra L. Kniffin - reorganized : 11/19/2003
Sonja A. Rasmussen - updated : 3/12/2001
Victor A. McKusick - updated : 2/10/1999
Victor A. McKusick - updated : 1/6/1999

*Link no longer available*

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EXTERNAL LINKS:

Massively parallel sequencing and identification of genes for primary lymphoedema: a perfect fit  Aug 2011

Wiley OnLine

Molecular characterization of dermal lymphatic endothelial cells from primary lymphedemaskin. Mar 2011 

Mary Ann Liebert

Primary lymphedema of limbs Dec 2010 

EM/Consulte


Home-made compression stockings and shoes of a cotton-polyester material in the treatment of primary congenital lymphedema. Dec. 2010 

PubMed Central

Early primary lymphoedema. A condition to remember Dec 2010 

Elsevier

Lymphedema, Hereditary


WebMD

Hereditary palmoplantar keratoderma associated with primary (congenital) lymphedema.


PubMed

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Hereditary lymphedema I

Raul Martinez, MD

Unidad Regiomontana de Diagn?stico, Monterrey, N.L. Address correspondence to Raul Martinez (rmtzsal@intercable.net), Unidad Regiomontana de Diagnostico, 5 de Mayo # 403 Pte., Monterrey, N.L., México. CP. 64000.

Synonyms: Nonne-Milroy lymphedema1,2. Lymphedema, early-onset. Primary congenital lymphedema.

 

Definition: Lymphedema is a chronic tissue swelling that is most commonly manifested in a limb. This condition results from impaired lymph drainage in the presence of normal capillary filtration. It may be either primary in type, which implies an intrinsic abnormality of the lymph-conducting pathways or, secondary in type, which implies that external factors such as radiotherapy, severe infection, or surgical excision have damaged lymph drainage routes. Most forms of primary lymphedema are thought to be caused by a congenital abnormality of the lymphatic system.

True congenital lymphedema, or hereditary lymphedema type I (OMIM 153100), usually presents either at, or soon after, birth and may be associated with other congenital malformations3,4,5,6.

Onset of clinical symptoms in hereditary lymphedema type II (OMIM 153200) usually occurs during or near either puberty or the menopause. In 1962 was reported a congenital chylous ascites in an affected infant, whose father had recurrent swelling of the scrotum beginning at the age of 20 years7. In 1964 pleural effusion was observed8. In 1965, Esterly described one child with congenital edema of the hands, as well as bilateral involvement of the legs and feet9

History: Although postnatal clinical diagnosis of this condition is relatively easy, there is only one prenatally diagnosed case described in the literature10.

Prevalence:  Nonne-Milroy lymphedema or hereditary lymphedema I is a relatively rare condition, whose occurrence is estimated to be around 1-2:10,000

Etiology:  The defect shows an autosomal dominant pattern of inheritance with reduced penetrance (80-84%), variable expressivity and variable age of onset from prenatal to 55 years. The disease has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35.

Pathogenesis:   It has recently been demonstrated that this region (5q34-q35) contains the FLT4 locus encoding the vascular endothelial growth factor receptor-3 (VEGFR-3), whose mutations interfere with normal vascular lymphatic function11,12.

Sonographic findings: The disease has variable expressivity and must be suspected in those fetuses with distal subcutaneous edema of the extremities, most frequently of the lower limbs, but the hands can also be involved. Findings can be present in one extremity or in all of them, and there is no concordance in the time of appearance and degree of involvement of each extremity. Occasionally, persistent or transient pleural effusion and ascites can be found.  The rest of the examination is normal.

Differential diagnosis: The following dysmorphic syndromes must be considered: Turner, Noonan, microcephaly-lymphedema, and hydrops.

Associated anomalies:  There are reports of associations with distichiasis4, hydroceles, atrial septal defect, and characteristic facial changes6

Prognosis:   Edema, particularly severe below the waist, sometimes complicated with papillomatosis and nail changes.

Management:   Several individuals ware compression stockings, which are effective in containing the edema, whereas those who are more severely affected attend hospital for compression pumping to reduce limb size prior to being fitting for compression hosiery.    

http://www.thefetus.net/page.php?id=358

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LYMPHEDEMA, HEREDITARY, II

Alternative titles; symbols

MEIGE LYMPHEDEMA
LYMPHEDEMA, LATE-ONSET
LYMPHEDEMA PRAECOXGene map locus 16q24.3

TEXT

A number sign (#) is used with this entry because of evidence that hereditary lymphedema type II is caused by mutation in the forkhead family transcription factor gene MFH1 (FOXC2; 602402). Allelic disorders with overlapping features include the lymphedema-distichiasis syndrome (153400), lymphedema and ptosis (153000), and lymphedema and yellow nail syndrome (153300). Also see hereditary lymphedema type I, or Milroy disease (153100). 30 MEDLINE Neighbors

CLINICAL FEATURES

Edema, particularly severe below the waist, develops about the time of puberty. Meige (1898) described 8 cases in 4 generations without male-to-male transmission. Goodman (1962) reported the condition in 2 sisters and a brother with presumed normal parents who were not known to be related. Herbert and Bowen (1983) described a kindred with many cases of lymphedema of postpubertal onset. Involvement of the upper limbs (as well as the lower limbs), face, and larynx and, in one, a persistent pleural effusion were notable features. Scintilymphangiography indicated paucity or absence of lymph nodes in the axillae and above the inguinal ligaments. Chronic facial swelling resulted in a characteristic appearance of affected members including puffiness, shiny skin, deep creases, and, in some, excessive wrinkling. Emerson (1966) noted similar facial features and remarked on the possible erroneous diagnosis of myxedema. 30 MEDLINE Neighbors

Herbert and Bowen (1983) noted the difficulties of nosology. For example, because lymphedema and yellow nail syndrome has yellow or dystrophic nails as a variable feature, this could be the same disorder. They pointed also to the association of late-onset lymphedema with deafness (Emberger et al., 1979) and with primary pulmonary hypertension and cerebrovascular malformations (152900; Avasthey and Roy, 1968). 30 MEDLINE Neighbors

Figueroa et al. (1983) reported the association of cleft palate. In their family, the mother, with only lymphedema praecox of the legs, gave birth to 5 sons, 3 of whom had both lymphedema of the legs and cleft palate. A mild form of lymphedema affecting mainly the medial aspect of both ankles in a 21-year-old son was pictured. 30 MEDLINE Neighbors

Andersson et al. (1995) described a family in which 3 individuals, a grandmother, her son and her grandson, had onset of lymphedema in their mid-20s or 30s. The grandson was 23 years old when he had his first episode of lymphedema, which was thought to be due to thrombophlebitis. During the ensuing decade, he had episodic waxing and waning of lymphedema of both lower limbs and was treated with anticoagulant therapy. At the age of 35, he developed lymphangiosarcoma on the inner right thigh and died of metastases some months later. Lymphangiosarcoma, usually associated with postmastectomy lymphedema, had not been described previously in late-onset hereditary lymphedema. Andersson et al. (1995) raised the question of whether a genetic predisposition to malignancy combined with the lymphedema was etiologically significant. There seemed to be an unusually high frequency of cancer (uterine, colon, lung, prostate, breast, and bone) in the proband's family. 30 MEDLINE Neighbors

MOLECULAR GENETICS

Finegold et al. (2001) found a mutation in the FOXC2 gene (602402.0007) in a family with Meige lymphedema and also in a family with yellow nail syndrome.

HETEROGENEITY

Finegold et al. (2001) noted that the phenotypic classification of dominantly inherited lymphedema includes Milroy disease (hereditary lymphedema I), Meige lymphedema (hereditary lymphedema II), lymphedema-distichiasis syndrome, lymphedema and ptosis, and yellow nail syndrome. The phenotypes reported in their 11 families overlapped the findings reported in Meige lymphedema, lymphedema-distichiasis syndrome, lymphedema and ptosis, and yellow nail syndrome, but not in Milroy disease. Milroy disease is associated with mutation in the FLT4 gene (136352), whereas mutations in the FOXC2 gene were observed in the 4 lymphedema syndromes that had phenotypic overlap.

SEE ALSO

Juchems (1963); Osterland (1961); Wheeler et al. (1981)

REFERENCES

1. Andersson, H. C.; Parry, D. M.; Mulvihill, J. J. :
Lymphangiosarcoma in late-onset hereditary lymphedema: case report and nosological implications. Am. J. Med. Genet. 56: 72-75, 1995.
PubMed ID : 7747790
2. Avasthey, P.; Roy, S. B. :
Primary pulmonary hypertension, cerebrovascular malformation, and lymphoedema of the feet in a family. Brit. Heart J. 30: 769-775, 1968.
PubMed ID : 5718986
3. Emberger, J. M.; Navarro, M.; Dejean, M.; Izarn, P. :
Surdi-mutite, lymphoedeme des membres inferieurs et anomalies hematologiques (leucose aigue cytopenies) a transmission autosomique dominante. J. Genet. Hum. 27: 237-245, 1979.
PubMed ID : 295075
4. Emerson, P. A. :
Yellow nails, lymphoedema, and pleural effusions. Thorax 21: 247-253, 1966.
PubMed ID : 5914998
5. Figueroa, A. A.; Pruzansky, S.; Rollnick, B. R. :
Meige disease (familial lymphedema praecox) and cleft palate: report of a family and review of the literature. Cleft Palate J. 20: 151-157, 1983.
PubMed ID : 6342849
6. Finegold, D. N.; Kimak, M. A.; Lawrence, E. C.; Levinson, K. L.; Cherniske, E. M.; Pober, B. R.; Dunlap, J. W.; Ferrell, R. E. :
Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum. Molec. Genet. 10: 1185-1189, 2001.
PubMed ID : 11371511
7. Goodman, R. M. :
Familial lymphedema of the Meige's type. Am. J. Med. 32: 651-656, 1962.
8. Herbert, F. A.; Bowen, P. A. :
Hereditary late-onset lymphedema with pleural effusion and laryngeal edema. Arch. Intern. Med. 143: 913-915, 1983.
PubMed ID : 6679236
9. Juchems, R. :
Das hereditaere Lymphoedem, Typ Meige. Klin. Wschr. 41: 328-332, 1963.
10. Meige, H. :
Dystrophie oedemateuse hereditaire. Presse Med. 6: 341-343, 1898.
11. Osterland, G. :
Beobachtungen zum Nonne-Milroy-Meige-Syndrom. Z. Menschl. Vererb. Konstitutionsl. 36: 108-117, 1961.
PubMed ID : 14482593
12. Wheeler, E. S.; Chan, V.; Wassman, R.; Rimoin, D. L.; Lesavoy, M. A. :
Familial lymphedema praecox: Meige's disease. Plast. Reconst. Surg. 67: 362-364, 1981.
PubMed ID : 7232571

CONTRIBUTORS

George E. Tiller - updated : 10/22/2001

CREATION DATE

Victor A. McKusick : 6/2/1986

EDIT HISTORY

carol : 11/19/2003

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=153200

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