PRIMARY LYMPHEDEMA

TYPES OF PRIMARY LYMPHEDEMA

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There are three main types of primary hereditary lymphedema.

Hereditary Primary Lymphedema I - Milroy's Disease

Related Terms: Nonne-Milroy lymphedema, Milroy's Disease, Primary congenital hereditary lymphedema, hereditary lymphedema I, Nonne-Milroy-Meige disease

Milroy's Syndrome is an old term used to describe hereditary congenital lymphedema. It is a congenital familial primary lymphedema which results from vertical autosomal inheritance of a single gene. The gene has been identified as VEGFR3. The condition usually presents itself at birth with the swelling of one or even both legs.

If the condition is unilateral (single leg), the other leg may continue in the latency stage for years before expressing itself. The same is indicated for arm lymphedema.

It is the rarest of the inherited lymphedema, accounting for approximately 2% of hereditary lymphedemas.

Hereditary lymphedema was first described by Nonne in 1891, however in 1892 Dr. William F. Milroy described a missionary who had returned from work in India who had swollen legs his entire life. His mother likewise was afflicted with the same condition. Milroy had also, previously studied the 250 year history of a family and had been able to identify 22 persons with this condition through 6 generations. He was also able to pinpoint when the condition entered the family through a marriage in 1768.

Diagnosis

Basic diagnosis can be made by the fact that swelling (generally of the legs) presents at birth and there is a family history of similar swelling. Currently the most precise diagnosis can be made by a lymphoscintigraphy test. In this test a radioactive substance is injected into the limb and is traced on a computer screen. Through this method the exact location of the lymphatic blockages can be identified.

Etiology

The cause of Milroy's Syndrome is a break in the VEGFR3 gene.

Complications

The usual complications involved with the condition include fibrosis of the limb tissues, cellulitis (and or lymphangitis and erysipelas infections). Other complications made include involvement of the genitalia, pain, skin conditions and in very rare situations lymphangiosarcoma.

Treatment

Decongestive therapy is the most widely accepted form of treatment. There is no cure for Milroy's but the condition can be managed by early diagnosis and treatment.

Prognosis

Long term prognosis is excellent is the condition is identified early and treatment begins so after the diagnosis is made.

Stages

LATENCY STAGE
Lymphatic transport capacity is reduced
No visible/palpable edema
Subjective complaints are possible

STAGE I
(Reversible Lymphedema)
Accumulation of protein rich edema fluid
Pitting edema
Reduces with elevation (no fibrosis)

STAGE II
(Spontaneously Irreversible Lymphedema)
Accumulation of protein rich edema fluid
Pitting becomes progressively more difficult
Connective tissue proliferation (fibrosis)

STAGE III
(Lymphostatic Elephantiasis)
Accumulation of protein rich edema fluid
Non pitting
Fibrosis and sclerosis (severe induration)
Skin changes (papillomas, hyperkeratosis, etc.)

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Noone-Milroy-Type Hereditary Lymphedema

Also known as Lymphedema I, this disorder presents as brawny edema usually of the lower extremity. The diagnosis is usually made at birth. Tissue swelling occurs distally or proximally in the involved limbs, and either hypoplasia or hyperplasia of the lymphatics has been found.

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Hereditary Primary Lymphedema Type II - Lymphedema Praecox Meige

See also: Nonne-Milroy-Meige Syndrome, Meige's lymphedema, Hereditary lymphedema II, familial lymphedema praecox

Form of primary hereditary lymphedema that starts at or around the time of puberty. The affected limbs are generally the legs.

Named after French physician Dr. Henri Meige who first described hereditary lymphedema in 1891. This form of lymphedema which usually presents itself at or during puberty is the most common of the hereditary lymphedemas, account for 65-80% of all diagnosed cases.

Meige-Type Lymphedema

Also known as Lymphedema II, this syndrome is similar to Lymphedema I but the onset of peripheral edema occurs during the second to the fifth decades. The legs are the most commonly involved, and lymphangiography reveals hypoplasia of peripheral lymphatics with dilation of lymphatic trunks.

Diagnosis

Basic diagnosis can be made by the fact that swelling (generally of the legs) presents during puberty and there is a family history of similar swelling. Currently the most precise diagnosis can be made by a lymphoscintigraphy test. In this test a radioactive substance is injected into the limb and is traced on a computer screen. Through this method the exact location of the lymphatic blockages can be identified.

Etiology

The cause of Lymphedema Praecox is a break in the VEGFR3 gene. The gene FOXC2 is implicated and there is also suspect third lymphedema gene.

Complications

Other Indications

Related conditions may also include yellow nail syndrome, pulmonary hypertension, cerebrovascular malformations and distichiasis

Treatment

Decongestive therapy is the most widely accepted form of treatment. There is no cure for Lymphedema praecox but the condition can be managed by early diagnosis and treatment.

Prognosis

Long term prognosis is excellent if the condition is identified early and treatment begins so after the diagnosis is made.

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Hereditary Primary Lymphedema Type III - Lymphedema Tarda

See also: Delayed Onset lymphedema, Hereditary lymphedema tarda

Form of primary hereditary lymphedema that expresses itself during middle age (generally onset 35+ years). Swelling generally occurs in the legs and may involve either one or both limbs. There is a higher incidence of lymphedema tarda among females than males.

This form of inherited lymphedema accounts for approximately 10% of those with primary lymphedema.

Diagnosis

Basic diagnosis can be made by the fact that swelling (generally of the legs) unexpectedly and there is a family history of similar swelling. Currently the most precise diagnosis can be made by a lymphoscintigraphy test. In this test a radioactive substance is injected into the limb and is traced on a computer screen. Through this method the exact location of the lymphatic blockages can be identified.

Etiology

The cause of lymphedema tarda is a break in the FOXC2 gene.

Complications

Treatment

Decongestive therapy is the most widely accepted form of treatment. There is no cure for lymphedema tarda but the condition can be managed by early diagnosis and treatment.

Prognosis

Long term prognosis is excellent is the condition is identified early and treatment begins so after the diagnosis is made

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LYMPHOEDEMA ASSOCIATION OF AUSTRALIA

What Are the Different Kinds of Primary Lymphoedema?

There are many different kinds of primary lymphoedema. Some are hereditary, but most are not. The list is far from complete. There are many syndromes which include lymphoedema, but they are rare syndromes. Listed below are a few of the identified syndromes.

Idiopathic Lymphoedema -Not Running in Families

This is the most common form of primary lymphoedema. As the name implies, this is primary lymphoedema of an unknown origin, and is not a part of a syndrome of other symptoms. It appears at birth or later on in an individual (more often female). Although it most commonly affects one lower extremity, it can affect any part of the body. It is not found in other family members because it is not hereditary and cannot be passed on to children. Lymphoscintigram findings will not show an obstruction as it would in acquired/secondary lymphoedema. Instead usually it will indicate a hypoplasia (underdevelopment of lymphatic vessels).

Primary Hereditary Lymphoedemas: Lymphoedemas Which Run in Families

Milroy’s Syndrome [also called Nonne-Milroy Syndrome]: Lymphoedema present at birth. Often the problem is a lack of initial lymphatics. [Autosomal Dominant,* chromosome 5]

Meige’s Syndrome : Like Milroy’s, but the lymphoedema does not appear until later: lymphoedema praecox (before 35) or lymphoedema tarda (after 35). [Autosomal Dominant]

Primary Hereditary Lymphoedemas with other symptoms

Yellow Nail Syndrome [Samman-White Syndrome]: Syndrome which includes discoloured thickened nails, pulmonary problems, and lymphoedema. Onset is usually childhood or early adulthood. [Autosomal Dominant]

Sharp-Aagenaes Syndrome: Distinguished by neonatal cholestasis (stoppage of bile excretion) with jaundice. The lymphoedema develops in early childhood and is equally seen in males and females. [Autosomal Recessive,* chromosome 15]

Lymphoedema with Distichiasis [Falls-Kertesz Syndrome]: As well as lymphoedema, there is an extra row of eyelashes (distichiasis); problems also include a widened spinal canal and other related problems. Onset is usually adolescence. [Autosomal Dominant, chromosome 16]

Avasthey-Roy Syndrome: As well as lymphoedema, there are arteriovenous malformations and pulmonary hypertension. Onset is usually adolescence. [Autosomal Dominant]

Hennekam’s Syndrome: Lymphoedema of face, genitals, and limbs; the face and nose are flat, the mouth narrow, the chin large, the ear malformed, the eyes protruding, the fingers can be webbed, the thumb large. There can be mild mental retardation. [Autosomal Recessive]

Noonan’s Syndrome: Includes webbed neck, protruding upper chest, receding lower chest, cardiomyopathy, short stature. Appears very similar to Turner’s Syndrome, below, except is not sex-linked.. [Autosomal dominant, chromosome 12]

Jeken’s Syndrome: Includes mental retardation, abnormal fat distribution at buttocks, and ataxia. Lymphoedema onset is during infancy. [Autosomal recessive, chromosome 16]

Figueroa Syndrome: Cleft palate; lymphoedema starts during childhood or adolescence. [Autosomal dominant]

Primary Lymphoedemas Associated with other Syndromes- Do Not Run In Families

Klippel-Trenaunay-[Weber] Syndrome: Venous and arterial alterations are present; when the lymph vessels are involved, they are frequently varicose. In Weber’s Syndrome, the bones of a limb are also hypertrophied (larger).[not hereditary]

Turner Syndrome: Affects only females because it is sex-linked.* Frequently the lymphatic system, (specifically the valves), is underdeveloped, resulting in childhood lymphoedema. This sometimes resolves by adolescence. Other features of Turner’s Syndrome include short stature, infertility, and sometimes problems with the heart, kidney, or thyroid.(XO instead of XX chromosome; not hereditary]

*Some Basic Genetics Terms:

Autosomal: a gene that is not on the sex-linked chromosome(x and y are the sex-linked chromosomes)

Dominant: only one of these genes must be present for the trait to exhibit itself

Recessive: the gene must be present from both parents for the trait to exhibit itself; a person with only one of the genes is said to be a carrier.

Incomplete penetrance: the situation when the dominant gene or two recessive genes are present, so the person should exhibit the trait, but in a certain percentage of cases, this does not happen

Ackowledgement

Lymphoedema Association of Australia[/b]
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PRIOR STUDIES OF PRIMARY LYMPHEDMEA

Isolated congenital hereditary lymphedema, now known as Nonne-Milroy Disease, was described by Milroy in 1892. The diagnostic criteria consisted of hereditary, congenital, chronic, and permanent lymphedema, which is not present above the waist, is firm but pitting to the touch, and does not affect longevity. However, exceptions such as one case of lymphedema praecox and one with spontaneous recovery were noted. The original paper described a family of 97 members with 22 affected individuals in six generations (Milroy, 1892).

Milroy attempted a follow-up investigation of this family thirty-five years later, at which time he identified thirty additional descendants in the fifth, sixth, and seventh generations. Since only two of these individuals were affected, he concluded that the disease was disappearing from the family, quite possibly by reason of attenuation of the trait through marriage with normal persons." However, a truly autosomal dominant disease would not be expected to show attenuation, and Milroy conceded that because many family members were lost to follow-up, this data was neither complete nor dependable (Milroy, 1928).

The first and only linkage study of congenital hereditary lymphedema was reported by John R. Esterly in 1965. The family he reported consisted of fifteen congenitally affected individuals in three generations, which included a reportedly affected stillborn female. Esterly's group examined all living affected family members, and a diagnosis of Milroy's Disease was confirmed. No linkage was demonstrated to red blood cell antigens, haptoglobin, phenylthiocarbamide tasting, or rate of isoniazid inactivation: some of the few polymorphic markers which were available at that time (Esterly, 1965).

In addition Esterly analyzed the 22 previously documented pedigrees for inheritance pattern, sex ratio of affected individuals, and ratio of affected to unaffected family members. Including Esterly's family, there were 152 affected people, among an unknown total number, in 23 families. Although lymphedema has been shown to affect three times more females than males in the general population, the sex ratio of all affected individuals in these families was 66 males to 81 females (5 were of unknown sex). Among the offspring of affected individuals, the ratio of affected to unaffected was 82:91, which is compatible with a simple autosomal dominant trait (Esterly, 1965). However, there were several families with reduced penetrance, and much of the data was incomplete or relied entirely on family reports. In addition, mild lymphedema is often difficult to detect, even when it is familial and congenital.

If only the families without skipped generations were included, the ratio of affected to unaffected individuals in at risk sibships changed to 50:46, and the sex ratio became 24:25. Esterly concluded that although all pedigrees were consistent with simple autosomal dominant inheritance, a second mode of inheritance may explain the excess of females in some of the families (Esterly, 1965).

Several investigators have addressed the preponderance of affected females with primary lymphedema. Some researchers have suggested the possibility of a sex-linked (X chromosome) modifier gene. Hormonal factors such as pregnancy and menstruation may also result in a greater penetrance of lymphedema praecox and tarda in females or increased expression of congenital lymphedema after menarche. However, the most plausible explanation for the excess of females with lymphedema is ascertainment bias because females may be more likely to report symptoms and seek treatment. Although three times more females are affected with primary lymphedema in the general population, this ratio drops to below two in sibships of many families with Milroy's or Meige's Disease.

http://www.pitt.edu/~genetics/lymph/previous.htm

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FOR FURTHER INFORMATION:

Primary Lymphedema - Milroy's Disease

Excerpt from Milroy Disease

http://www.emedicine.com/med/byname/milroy-disease.htm

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MEIGE LYMPHEDEMA, LYMPHEDEMA, LATE-ONSET, LYMPHEDEMA PRAECOX

Online Mendelian Inheritance in Man

John Hopkins University

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

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Pat O'Connor

Lymphedema People / Advocates for Lymphedema

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Lymphedema Glossary

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Lymphedema People - Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

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All About Lymphedema

For our Google fans, we have just created this online support group in Google Groups:

Homepage: http://groups-beta.google.com/group/All-About-Lymphedema

Group email: All-About-Lymphedema@googlegroups.com

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Lymphedema Friends

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Lymphedema People New Wiki Pages

Have you seen our new “Wiki” pages yet? Listed below are just a sample of the more than 140 pages now listed in our Wiki section. We are also working on hundred more. Come and take a stroll!

Lymphedema Glossary

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Lymphedema

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Arm Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=arm_lymphedema

Leg Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=leg_lymphedema

Acute Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=acute_lymphedema

The Lymphedema Diet

http://www.lymphedemapeople.com/wiki/doku.php?id=the_lymphedema_diet