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MILROY'S SYNDROME

MILROY'S DISEASE

Congenital Lymphedema

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Milroy's Syndrome

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Related Terms: Nonne-Milroy lymphedema, Milroy's Disease, Primary congenital hereditary lymphedema, hereditary lymphedema I, Nonne-Milroy-Meige disease, hereditary tropholymphoedema syndrome; idiopathic hereditary lymphedema, lymphoedema; lymphedema, early onset type; trophoedema hereditarium (chronicum extremitatum inferiorum); tropholymphoedema, elephantiasis congenita hereditaria, familial hereditary oedema 

See also: Lymphedema              

http://www.lymphedemapeople.com/thesite/all_about_lymphedema.htm

Disorder Subdivisions - Lymphedema
        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

Milroy's Syndrome

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,  inflammation and various defects, including distichiasis, extradural cysts, vertebral anomalies, cerebrovascular malformations, yellow nails.

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. Other treatments involved will focus on the complications such as infections, pain and associated skin problems.

Other therapies used may include compression pump therapy and surgical procedures.

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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Stages of Milroy's Syndrome (Lymphedema)

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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Fibrosis in Milroy's Syndrome

Long standing lymphedema causes a condition known as fibrosis. As the fluid continually collects in a limb, it becomes hard and dense. With each stage of lymphedema there is also a change in the tissue texture of a limb.

With stage one the tissue is still much like normal tissue, its just satiated with fluid. As the swelling continues and as he fluid changes to that protein-rich fluid referred to a lymphorrea, you enter into stage two. In this stage, the tissue become very similar to a grape (best image I can think of). Already it is becoming much more difficult for antibiotics to reach bacteria and it becomes less response to the decongestive therapy.

At stage three, the tissue become similar to one of those old synthetic kitchen sponges, the ones that become rock hard when they are dry.

This is the very real serious side affect of stage three lymphedema. This type of tissue increases potential of persistent and very hard to treat cellulitis or lymphangitis.

The denseness of the limb prohibits antibiotics from reaching the infecting bacterium and it is often able to survive in pockets of fibrotic tissue. These pockets act as a septic foci and after antibiotic treatment is completed, the infections will reappear.
Generally at this stage it is going to take IV antibiotics to deal with any infection because oral antibiotics just are not able to penetrate this mass of hard tissue.

Also, as the fibrosis intensifies you become more susceptible to deep venous thrombosis (DVT) and other circulatory problems. You may also start to experience neuropathy as the pressure of this tissue compresses nerves within the limb.

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Decongestive Therapy and Milroy's Syndrome

Manual Lymphatic Drainage (MLD): is a unique, therapeutic method of stimulating the movement of fluids in the tissues. The gentle, rhythmic, pumping, massage movements follow the direction of lymph flow and produce rapid results. It assists the cutaneous lymphatics in picking up and removing not just fluids, but all the waste products, protein particles and debris from our system. It also is successful in breaking fibrosis and fibrotic areas of a lymphodemous limb.

This treatment was created and developed Danish therapists Dr. Emil Vodder and his wife, Estrid, in the 1930's and was introduced in Paris in 1936. They are also credit with creating a specialty of medicine called Lymphology.

First brought to North America in 1982, the school is located in
Victoria, British Columbia, Canada. Before it was introduced the standard treatment course in North American was either a surgery called debulking or the use of compression machines wherein the limb was literally squeezed by pneumatic air pressure.

Comprehensive Decongestive Therapy (CDT) is used primarily in the treatment of lymphedema and venous insufficiency edema. It is a combination of MLD, bandaging exercises and skin care. CDT may also involve breathing exercises, compressive garments and dietary measures. A frequent indication for CDT is lymphedema caused by irradiation or surgery due to cancer. It can relieve edema, fibrosis and the accompanying pain and discomfort.

Also known as Complete Decongestive Physiotherapy (CDP), this treatment therapy was pioneered in the United States by Dr. Robert Lerner.

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Cellulitis and Milroy's Syndrome  

Acute Cellulitis is one of the complications of lymphedema. The patient may not be aware of the source of the etiology. Sometimes it may be a cut, mosquito bite, open wound or other infection in the body.

The first sign is increased or different quality of PAIN involving the lymphedema limb. The patients often describe this as a "flu like symptom or an ache" involving the Lymphedema arm or leg. This is usually followed by sudden onset of ERYTHEMA(redness, red streaks or blotches) on the involved limb. The HYPERTHERMIA(lymphedema limb becomes warm, hot) will follow and the patient may experience the CHILLS and even HIGH FEVER.

The early intervention and treatment with antibiotics will resolve this condition (it usually takes a very minimum ten day course of antibiotics). Only a Medical Doctor will be able to prescribe the Antibiotics, thus a consultation with a Doctor is necessary. Severe Cellulitis may require Inter venous Antibiotic treatment and hospitalization. Again, elevation of the affected limb is important.

During that phase the patient should NOT massage the Lymphedema limb, bandage, apply the pump, wear tight elastic sleeve or exercise excessively. Avoid the blood pressure and blood to be drawn from the involved arm. Keep the limb elevated as much as possible while resting. Once the symptoms dissipate the treatment MLD/CDP should be initiated.

How do we prevent this infection? The patient should be careful with daily activities and take all precautions to protect the skin (wear gloves when gardening, cleaning with detergents, etc.. ).

 If an injury to skin occurs on the Lymphedema limb it is necessary to clean the wound with alcohol or hydrogen peroxide and apply Neosporin/Polysporin antibiotic ointment. If the symptoms progress seek the attention of a physician immediately.

It is so very important to avoid getting cellulitus as it further destroys the lymphatic system. Allowed to spread or continue it can become systemic and can lead to gangrene, amputation of the limb or even death.

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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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Prenatal diagnosis of Milroy's primary congenital lymphedema.

Makhoul IR, Sujov P, Ghanem N, Bronshtein M.

Department of Neonatology, Rambam Medical Center, Bat-Galim, Haifa, Israel. Makhoul@rambam.health.gov.il

Milroy's primary congenital lymphedema (PCL) (hereditary lymphedema type I, Milroy disease) is present at birth, and mostly affects the dorsal aspects of feet. It is mostly a life-long condition but does not affect longevity. Complications are rare except for chronic discomfort and warmness of affected areas. PCL is an autosomal dominant disease with incomplete penetrance due to a mutation in the gene locus encoding for VEGFR3 with resultant dysgenesis of microlymphatic vessels. We report on two fetuses where ultrasonographic examination at 15 weeks of gestation showed significant edema of the dorsal aspects of both feet with no evidence of other major malformations. Whereas in one fetus the edema resolved completely, it persisted in the second fetus and proved after birth to be of lymphedematous nature. To the best of our knowledge, this is the first report of early prenatal diagnosis of primary congenital lymphedema via fetal ultrasonographic examination and of spontaneous resolution of lymphedema during fetal life. Copyright 2002 John Wiley & Sons, Ltd.

Pub Med

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12224079&itool=iconabstr

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Primary Lymphedema - Milroy's Disease

Excerpt from Milroy Disease

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

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Milroy's Syndrome - Genetic Cause

Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase.

Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M.

Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology and Universite catholique de Louvain, B-1200 Brussels, Belgium.

Hereditary lymphedema is a chronic swelling of limbs due to dysfunction of lymphatic vessels. An autosomal dominant, congenital form of the disease, also known as "Milroy disease," has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35. This region contains a good candidate gene for the disease, VEGFR3 (FLT4), that encodes a receptor tyrosine kinase specific for lymphatic vessels. To clarify the role of VEGFR3 in the etiology of the disease, we have analyzed a family with hereditary lymphedema. We show linkage of the disease with markers in 5q34-q35, including a VEGFR3 intragenic polymorphism, and we describe an A-->G transition that cosegregates with the disease, corresponding to a histidine-to-arginine substitution in the catalytic loop of the protein. In addition, we show, by in vitro expression, that this mutation inhibits the autophosphorylation of the receptor. Thus, defective VEGFR3 signaling seems to be the cause of congenital hereditary lymphedema linked to 5q34-q35.

Pub Med

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10856194&itool=iconabstr

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Recurrent septic arthritis and Milroy's disease.

Albornoz MA, Myers AR.

Division of Rheumatology and Immunologic Diseases, Temple University Health Sciences Center, Philadelphia, PA 19140.

Milroy's disease is a rare disorder characterized by multiple physical anomalies, the most prominent of which is lymphedema of one or both lower extremities. We describe, with a review of proposed pathogenetic mechanisms, a patient with Milroy's disease who, over a 13-year period, manifested at least 14 isolated episodes of septic arthritis of the left knee. Recurrent septic arthritis associated with Milroy's disease has not been reported previously.

Medline Plus

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=89178376

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LYMPHANGIOSARCOMA  ON   CONGENITAL  LYMPHOEDEMA - Milroy's Syndrome

Key Words:  Chronic  Lymphoedema Lymphangiosarcoma,  Milroy disease

Case report: 

A 31 years old white male complaining of congenital – familial form-   non previously treated lymphoedema  - Milroy disease - was admitted with the aspect seen - Images  1,2,3 -. A biopsy  revealed the presence of lymphangiosarcoma – Images 4,5,6 -. No evidence of metastatic disease was clinically evident. High AK amputation was indicated and performed followed by prosthetic extremity replacement. No complementary treatment was done. Patient is free of the disease three years after operation and no evidence recurrence has been noticed so far.. 

Lymphoedema (1) may be primary or secondary to the presence of other disease and/or to the consequences of surgery or trauma (2). Primary lymphoedema may be congenital – Milroy´s disease – or may occur at any phase of life but it most commonly appears at puberty – Meig’s disease -. Secondary lymphoedema is encountered more often. The most prevalent worldwide cause of lymphoedema is filariasis, which is particularly common in south-east Asia and Africa. In Western countries postsurgical lymphoedema of the extremity prevails. Complications of chronic limb lymphoedema include recurrent cellulitis and lymphangiosarcoma albeit other tumors such squamous-cell carcinoma (3,4), b-cell lymphoma (5)  and angiosarcoma  (6,7,8,9) has been reported. 

In cases of long-lasting or congenital lymphoedema the finding of ulceration, violaceous nodules or papules, or apparent traumatic ecchymoses should act as a diagnostic beacon warning of dangers. A case is reported of a high-grade lymphangiosarcoma developing in a patient with congenital hereditary lymphoedema (Milroy's disease) in a familial form (10). Hereditary lymphoedemas that are not associated with other malformations usually affect the lower limbs and are inherited in an autosomal dominant fashion. These non-syndromic hereditary lymphoedemas are categorized by their age of onset, being either congenital (Milroy disease) or having an onset in childhood or around puberty (Meige disease) (11). Development of  lymphangiosarcoma is  usually associated with post-mastectomy lymphoedema, has  been described in late-onset hereditary lymphoedema. There is a high incidence of multiple primary tumors in association with lymphangiosarcoma in the literature (12). 

Lymphangiosarcoma is a rare, aggressive, vascular neoplasm arising in chronic congenital or acquired lymphedema. Although it is most frequently associated with post-mastectomy lymphedema (Stewart-Treves's syndrome), lymphangiosarcoma can exceptionally arise in congenital hereditary lymphedema (11)(Milroy's syndrome and Meige's syndrome) and non-hereditary lymphoedema (congenital, praecox or forme tarde lymphoedemas) (13).

The risk of appearance of lymphangiosarcoma following mastectomy and radiation therapy has been recently analyzed. Between 1954 and 1983, 7620 patients were treated for breast carcinoma at Institut Gustave Roussy (France) (14). Of these patients, 6919 were followed for at least 1 year. Out of these, 11 presented with sarcomas thought to be induced by irradiation, 2 of which were Steward-Treves Syndrome, and 9 of which were sarcomas within the irradiated fields. All histological slides were reviewed and a comparison with those of breast cancer was done. The sites of these sarcomas were: parietal wall, 1 case; second costal cartilage, 1 case; infraclavicular region, 1 case; supraclavicular region, 2 cases; internal third of the clavicle, 2 cases; axillary region 2 cases; and the internal side of the upper arm (Stewart-Treves syndrome), 2 cases. The median age of these 11 patients at the diagnosis of sarcomas was 65.8 (49-83). The mean latent period was 9.5 years (4-24). Three patients underwent radical mastectomy and nine modified radical mastectomy. Only one patient received chemotherapy. The radiation doses received at the site of the sarcoma were 45 Gy/18 fr. for 10 cases and 90-100 Gy for 1 case (due to overlapping between two fields). The histology was as follows: malignant fibrous histiocytoma, 5 cases; fibrosarcoma, 3 cases; lymphangiosarcoma, 2 cases; and osteochondrosarcoma, 1 case. The median survival following diagnosis of sarcoma was 2.4 years (4 months-9 years). Two patients are still alive: one with recurrence of her breast cancer, the other in complete remission, with 7 and 3 years follow-up, respectively. All other patients died from their sarcomas. The cumulative incidence of sarcoma following irradiation of breast cancer was 0.2% (0.09-0.47) at 10 years. The standardized incidence ratio (SIR) of sarcoma (observed n# of cases (Obs)/expected n# of cases (Exp) computed from the Danish Cancer Registry for the same period) was 1.81 (CI 0.91-3.23). This is significantly higher than one, with a p = 0.03 (One Tailed Exact Test). The mean annual excess (Obs-Exp)/100.000 person-years at risk during the same period/(100,000) was 9.92. This study suggests that patients treated by radiation for breast cancer have a risk of subsequent sarcomas that is higher than the general population. However, the benefit from adjuvant radiation therapy in the treatment of breast cancer exceeds the risk of second cancer; therefore, the potential of radiation-induced sarcomas should not be a factor in the selection of treatment for patients with breast cancer 

Moreover, we emphasized the importance of regular clinical controls in all patients affected by chronic lymphoedema (15,16). In fact, although the prognosis of this neoplasm is very poor, a prompt diagnosis and a rapid, ablative surgery associated with radiation therapy can increase the possibility of survival of these patients (17,18). Chemotherapy with intraarterial mitoxantrone and placitaxel with ex vivo previous sensitivity test seems a current adequate complementary approach (19).

http://www.sc.ehu.es/scrwwwsr/kirurgia/Kirurgia2003b/Linfangiosarcoma.htm  

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Primary congenital lymphedema (Milroy's)

Véronique Mirlesse MD*, Ronaldo Levy MD*, Geneviève Brodaty MD*, Pascale Sonigo MD**, Dominique Teillac MD***, Luc Gourand, MD*, Fernand Daffos MD* Fernando Heredia MD"

*  Service de médecine foetale, Institut de Puériculture et Périnatalogie, Paris.
** Service de radio-pédiatrie, Hopital Necker Enfants Malades, Paris
*** Service de dermatologie, Hopital Necker Enfants Malades, Paris
" Women"s Health Alliance, Nashville, Tennessee.

Synonyms: Hereditary lymphedema type I, Nonne-Milroy Lymphedema, early-onset lymphedema, primary congenital lymphedema.

Incidence: 1:33,000 newborn. Male to female ratio 1:2,3[1],[2]

Etiology: Autosomal dominant with incomplete penetrance. The gene mutation has been found near the most telomeric region of  5q35.3²,[8] There is also some evidence of 2 different sub-mutations or variants depending on the nucleotide substituted[9],[10],[11],[12],[13].

Pathogenesis:All the anomalies found are due to dysgenesis of lymphatic microvessels. These dysgenesis ranges from mild to severe and even to aplasia of both, the lymphatic capillaries and collectors[14],[15],[16].

Main features: Present in one or both legs at birth. Lymphedema of PCL persists throughout life but does not appear to affect longevity. As the patient matures, the overlying skin displays a slightly rosy hue, and the size of the edematous parts remains proportional to the remainder of the body. It can rarely present with genital edema, resembling sexual ambiguity[3].

Ultrasound appearance:This condition is suggested by the finding of an isolated edema of the dorsum of feet in the fetus, a normal karyotype and absence of other significant malformations.

Case report:

These are images obtained during a 28-week routine ultrasound examination. Fetal weight was over the 97th centile.

Fetal lower limbs: Edema of the lower limbs, specially the distal portions. Compare the width of legs and thighs.

Differential diagnosis:

• Non-lymphatic edema.
• Turner syndrome
• Noonan syndrome
• Lymphedema-distichiasis syndrome (double row of eyelashes)[4],[5]
• Lymphedema and ptosis syndrome.
• Meige lymphedema (Hereditary lymphedema type II, late-onset congenital lymphedema, lymphedema praecox)[6].
• Congenital recessive type lymphedema[7].

Possible complications:

Reported complications, although rare, have been reported:

• Intestinal lymphangiectasia[17].
• Bacterial infections of dorsal aspects of feet and toes[18].
• Recurrent septic arthritis[19].
• Angiosarcoma[20].
• Lymphangiosarcoma[21].

Management: If other fetal anomalies are ruled out, and fetal karyotype is normal, parental counseling concerning etiology, management, and possible complications is advisable.

http://www.thefetus.net/page.php?id=1035

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Milroy's Disease

Medscape

http://emedicine.medscape.com/article/299840-overview

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Milroy's Disease Treatment and Management

Medscape Reference

http://emedicine.medscape.com/article/299840-treatment

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Milroy's Disease - a parents view

http://tjmum.hubpages.com/hub/Milroys-Disease 

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What is Milroy's Disease?

http://www.netdoctor.co.uk/ate/heartandblood/202958.html

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Congenital lower limb enlargement in a newborn.

http://onlinelibrary.wiley.com/doi/10.1111/j.1525-1470.2010.01202.x/abstract

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Acupuncture Treatment

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Laser Treatment - Sara's Experience

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Liposuction Treatment

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Lymphedema Surgeries

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Lymphedema Treatments are Poorly Utilized

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Lymphedema Treatment Programs Canada

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Wholistic Treatment

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Microsurgeries

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Homeopathy

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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

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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.

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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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Updated Dec. 26, 2011