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milroys_syndrome

MILROY'S SYNDROME

MILROY'S DISEASE

Congenital Lymphedema, Hereditary lymphedema l

Nonne-Milroy lymphedema, Milroys 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, leg lymphedema,

See also: lymphedema

Related Articles: My Life with Lymphedema

My Life with Lymphedema and Lymphoma

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 mutation in the VEGFR3 gene.

Complications

1. Infections such as cellulitis, lymphangitis, erysipelas. This is due not only to the large accumulation of fluid, but it is well documented that lymphodemous limbs are localized immunodeficient and the protein rich fluid provides an excellent nurturing invironment for bacteria.

2. Draining wounds that leak lymphorrea which is very caustic to surrounding skin tissue and acts as a port of entry for infections.

3. Increased pain as a result of the compression of nerves usually caused by the development of fibrosis and increased build up of fluids. See Lymphedema and Pain Management.

4. Loss of Function due to the swelling and limb changes.

5. Depression - Psychological coping as a result of the disfigurement and debilitating effect of lymphedema.

6. Deep venous thrombosis again as a result of the pressure of the swelling and fibrosis against the vascular system. Also, can happen as a result of cellulitis, lymphangitis and infections.

7. Sepsis, Gangrene are possibilities as a result of the infections.

8. Possible amputation of the limb.

9. Pleural effusions may result if the lymphatics in the abdomen or chest are to overwhelmed to clear the lung cavity of fluids.

10. Skin complications such as dry skin, splitting, plaques and nodules, susceptibility to fungus and bacterial infections.

11. Chronic localized inflammations.

12. Pain ranging from mild in early lymphedema to severe in late stage lymphedema.

13. Lymphatic cancers which can include angiosarcoma, lymphoma; Kaposi's Sarcoma; lymphangiosarcoma (Stewart_treves Syndrome); Cutaneous T-Cell lymphoma; Cutaneous B-Cell lymphoma; Pseudolymphomatous Cutaneous Angiosarcoma. See also: Primary Lymphedema and Cancer for a discussion and Lymphatic Cancers Secondary to Lymphedema.

Note: These cancers are rare and are usually associated with long term, untreated or improperply treated lymphedema. Typically occuring in stage three or four; quite rare in stage two.

14. Skin complications possible in stages 3 and 4 include papillomatosis; placques including “cobblestone” appearing placque; dermatofibroma; Skin Tags; Warts and Verrucas; Mycetoma skin fungus; dermatitis and many lymphedema patients report increased problems with psoriasis; eczema and shingles. I would suspect this may be due to again, the immunocompromised condition of the arm or leg afflicted with lymphedema.

15. Documented but rare complications in late stage also can include Lymphomatoid Papulosis; Cutis Marmorata; Acroangiodermatitis; Dermatolymphangioadenitis (DLA); Papillomatosis cutis carcinoides

16. Debilitating joint problems. This is caused by a combination of the excess fluid weight and the constant inflammatory process that accompanies lymphedema. As we have gotten older, many lymphedemapatients are having total knee replacement, total hip replacement, or total shoulder replacement while others are experiencing carpal tunnel syndrome and are having carpal tunnel surgery or experiencing shoulder problems associated with lymphedema and must haverotator cuff surgery

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.

The preferred treatment today is decongestive therapy. The forms of therapy are complete decongestive therapy (CDT) or manual decongestive therapy (MDT), there are variances, but most involve these two type of treatment.

With these massage treatments, swelling is reduced and then the patient is fitted with a pre-measured custom pressure garment to keep the swelling down.

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 assistes the cutaneous lymphatics in picking up and removing not just fluids, but all the waste products, protein partical 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 pionered in the United States by Dr. Robert Lerner.

To insure you receive the proper treatment by a certified therapist you will need to know how to choose a lymphedema therapist, questions to ask, certifications and training they have received.

Other treatments include the use of compression pumps, surgery, microsurgery and newer approaches such as the use of lasers, liposuction, wholistic therapies and even acupuncture.

Pneumatic compression pumps have long been used for the treatment of lymphedema. However, clinical studies have indicated that there are two main complications involved with compression pump therapy for leg lymphedema.

First, the compression damages the superficial lymphatics, eventually creating worsening which leads to fibrosis, increased risk of infections and further complications.

Secondly, it has been demonstrated that 35% of patients, male and female, will develop genital lymphedema as a result of pump use. The reason for this is that the fluid is pushed into the abdomen and can overload the abdominal lymphatics and thus the fluid is NOT removed from the body.

Pneumatic compression pump is not recommended for leg lymphedema.

Lymphedema Bandaging

Lymphedema bandaging is one of the most powerful components in the treatment process. When a good bandage is applied, it will function as a custom-made compression garment, each and every time. While the extremity is reducing in size, the bandage is adapting to the new dimensions. A pre-made elastic garment will never have this adaptability, instead lymphedema patients should use what is referred to as a short stretch bandage.

It is said that the compression bandage contributes to approximately 50% of the reduction achieved with CDT. With this in mind, it is clear to proficiency in the bandaging techniques is crucial to achieve the best possible outcomes.

The compression bandage has the following effects:

It increases the effectiveness of the muscle pump mechanism. It increases the overall tension in the affected extremity and therefore reducing ultra filtration. It supports the skin while it is reducing in size.

Another critical area pertaining to the treatment, control and management of lymphedema, and that is exercise. Not only is it vital for our over all health, it helps in weight control and is important for the movement of lymph fluid through our body. No matter the stage of lymphedema, underlying medical conditions or age, everyone of us should have a plan for exercises for lymphedema.

Sometimes too, the process we must go through to get our treatment covered is maddening to say the least. You made need to learn how_to_file_a_health_insurance_appeal to reverse a coverage or treatment denial and you may even have to learn the process how to file a complaint against your insurance company with your state commissioner.

Seeking proper medical care that we need with lymphedema is how to choose a primary care doctor that understands and or even knows about lymphedema and in understandinding ”what type of doctor should I go to.”

Finally, a very important part of managing lymphedema is the lymphedema diet. We need to understand the importance of proper nutrition in overall health, wound healing, immune system function and weight control.

Prognosis

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

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.)

Tissue 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 the 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.

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.

Cellulitis and Milroy's Syndrome

Acute Cellulitis 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.

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.

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.

PubMed


Primary Lymphedema - Milroy's Disease

Excerpt from Milroy Disease

eMedicine


See Also:

Lymphedema Gene VEGFC

Lymphedema Gene FOXC2

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.

PubMed

Lymphatic dysfunction, not aplasia, underlies milroy disease

Microcirculation. 2010 May

Mellor RH, Hubert CE, Stanton AW, Tate N, Akhras V, Smith A, Burnand KG, Jeffery S, Mäkinen T, Levick JR, Mortimer PS.

Cardiac & Vascular Sciences (Dermatology), St George's Hospital Medical School, University of London, London, UK.

Abstract

Objective: Milroy disease is an inherited autosomal dominant lymphoedema caused by mutations in the gene for vascular endothelial growth factor receptor-3 (VEGFR-3, also known as FLT4). The phenotype has to date been ascribed to lymphatic aplasia. We further investigated the structural and functional defects underlying the phenotype in humans.

Methods: The skin of the swollen foot and the non-swollen forearm was examined by (i) fluorescence microlymphangiography, to quantify functional initial lymphatic density in vivo; and (ii) podoplanin and LYVE-1 immunohistochemistry of biopsies, to quantify structural lymphatic density. Leg vein function was assessed by colour Doppler duplex ultrasound.

Results: Milroy patients exhibited profound (86-91%) functional failure of the initial lymphatics in the foot; the forearm was unimpaired. Dermal lymphatics were present in biopsies but density was reduced by 51-61% (foot) and 26-33% (forearm). Saphenous venous reflux was present in 9/10 individuals with VEGFR3 mutations, including two carriers. Conclusion: We propose that VEGFR3 mutations in humans cause lymphoedema through a failure of tissue protein and fluid absorption. This is due to a profound functional failure of initial lymphatics and is not explained by microlymphatic hypoplasia alone. The superficial venous valve reflux indicates the dual role of VEGFR-3 in lymphatic and venous development.

PubMed

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

NIH

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 lymphedema - 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 form 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).

SC.EHU

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.

Longitudinal view , cross section and fetal leg MRI also show edema.

The baby boy was delivered uneventfuly and the following images show foot and toe edema.

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.

References


[1] Makhoul IR, Sujov P, Ghanem N, Bronshtein M. Prenatal diagnosis of Milroy”s primary congenital lymphedema. Prenat Diagn 2002 Sep;22(9):823-6

[2] Ferrell RE, Levinson KL, Esman JH, Kimak MA, Lawrence EC, Barmada MM, Finegold DN. Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet 1998 Dec;7(13):2073-8

[3] Sarda P, Jalaguier J, Montoya F, Bonnet H. Hereditary congenital lymphedema with pseudosexual ambiguity.J Genet Hum 1988 Aug;36(4):353-60

[4] Dale RF.Primary lymphoedema when found with distichiasis is of the type defined as bilateral hyperplasia by lymphography. J Med Genet 1987 Mar;24(3):170-1

[5] Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome.Am J Hum Genet 2000 Dec;67(6):1382-8

[6] Herbert FA, Bowen PA. Hereditary late-onset lymphedema with pleural effusion and laryngeal edema. Arch Intern Med 1983 May;143(5):913-5

[7] Mucke J, Hoepffner W, Scheerschmidt G, Gornig H, Beyreiss K. Early onset lymphoedema, recessive form–a new form of genetic lymphoedema syndrome. Eur J Pediatr 1986 Aug;145(3):195-8

[8] Evans AL, 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 1999 Feb;64(2):547-55

[9] Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 2000 Aug;67(2):295-301

[10] Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA,Alitalo K, Finegold DN. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.Nat Genet 2000 Jun;25(2):153-9

[11] Finegold DN, Kimak MA, Lawrence EC, Levinson KL, Cherniske EM, Pober BR, Dunlap JW, Ferrell RE. Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet 2001 May 15;10(11):1185-9

[12] Holberg CJ, Erickson RP, Bernas MJ, Witte MH, Fultz KE, Andrade M, Witte CL. Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenitalprimary lymphedema families. Am J Med Genet 2001 Feb 1;98(4):303-12

[13] Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997 May 30;276(5317):1423-5

[14] Partsch H, Urbanek A, Wenzel-Hora B. The dermal lymphatics in lymphoedema visualized by indirect lymphography. Br J Dermatol 1984 Apr;110(4):431-8

[15] Bollinger A, Isenring G, Franzeck UK, Brunner U. Aplasia of superficial lymphatic capillaries in hereditary and connatal lymphedema (Milroy”s disease). Lymphology 1983 Mar;16(1):27-30

[16] Pfister G, Saesseli B, Hoffmann U, Geiger M, Bollinger A. Diameters of lymphatic capillaries in patients with different forms of primary lymphedema. Lymphology 1990 Sep;23(3):140-4

[17] Wheeler ES, Chan V, Wassman R, Rimoin DL, Lesavoy MA. Familial lymphedema praecox: Meige”s disease. Plast Reconstr Surg 1981 Mar;67(3):362-4

[18] Mehta SD, Robinson RJ, Bern SA. Pedal manifestations of Milroy”s disease. J Am Podiatr Med Assoc 1996 Aug;86(8):400-2

[19] Albornoz MA, Myers AR. Recurrent septic arthritis and Milroy”s disease. J Rheumatol 1988 Nov;15(11):1726-8

[20] Offori TW, Platt CC, Stephens M, Hopkinson GB. Angiosarcoma in congenital hereditary lymphoedema (Milroy”s disease)–diagnostic beacons and a review of the literature. Clin Exp Dermatol 1993 Mar;18(2):174-7

[21] Brostrom LA, Nilsonne U, Kronberg M, Soderberg G. Lymphangiosarcoma in chronic hereditary oedema (Milroy”s disease). Ann Chir Gynaecol 1989;78(4):320-3

Fetus.net

Kaposiform hemangioendothelioma associated with Milroy's disease (primary hereditary lymphedema)

Méndez R, Capdevila A, Tellado MG, Somoza I, Liras J, Pais E, Vela D. Department of Pediatric Surgery, Children's Hospital Teresa Herrera, Complexo Hospitalario Juan Canalejo, A Coruña, Spain.

Keywords: Kaposiform infantile hemangioendothelioma, Milroy’s disease, primary lymphedema, vascular tumors

Kaposiform infantile hemangioendothelioma (KHE) is a rare recently characterized, locally aggressive, endothelial-derived neoplasm that occurs exclusively in the pediatric age group. Milroy-Nonne disease (primary hereditary lymphedema) is an uncommon congenital entity with familiar history of lower limb edema as typical clinical features. An 8-year-old boy developed a hard painless mass in the right leg 7 years after the diagnosis of congenital primary lymphedema of the right lower extremity. Histopathological analysis of the tumor showed the typical findings of the KHE. To our knowledge this is the first reported case of a KHE engrafting on this infrequent benign lymphatic anomaly.

Jpedssurg

Milroy's Syndrome from Gene Review

Summary

Disease characteristics. Milroy disease is characterized by lower-limb lymphedema, present at birth as pedal edema or developing soon after. Occasionally it develops later in life. The severity of edema shows both inter- and intrafamilial variability. Swelling is usually bilateral but can be asymmetric. The degree of edema can progress but in some instances can improve, particularly in early years. Other features sometimes associated with Milroy disease include hydrocele (37% of males), prominent veins (23%), upslanting toenails (14%), papillomatosis (10%), and urethral abnormalities in males (4%). Cellulitis, which can damage the lymphatic vessels, occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females.

Diagnosis/testing. Milroy disease is diagnosed by clinical findings and confirmed by molecular genetic testing. Lymphoscintigraphy can be performed; the characteristic finding is lack of uptake of radioactive colloid in the ilioinguinal lymph nodes caused by a paucity of lymphatic vessels or abnormal function of the vessels in the lower limbs. Molecular genetic testing for FLT4 (VEGFR3), the only gene known to be associated with Milroy disease, is available on a clinical basis.

Management. Treatment of manifestations: A lymphedema therapist may utilize fitted stockings and massage to improve the cosmetic appearance or decrease the size of the limb and reduce the risk of complications. Improvement in swelling is usually possible with use of properly fitted compression hosiery and/or bandaging. Prevention of secondary complications: Frequency of cellulitis can be reduced through good skin hygiene, prompt treatment of infections with antibiotics, and prophylactic antibiotics for recurrent episodes. Agents/circumstances to avoid: wounds to limbs; long periods of immobility with the legs in a dependent position; and medications that can cause increased leg swelling. Testing of relatives at risk: Evaluating relatives at risk ensures identification of those who will benefit from treatment early in the disease course.

Genetic counseling. Milroy disease is inherited in an autosomal dominant manner. Each child of an individual with Milroy disease has a 50% chance of inheriting the mutation. The proportion of cases caused by de novo mutations is not known. Ultrasonography in the third trimester of pregnancy may detect swelling of the dorsum of the feet and more extensive edematous states in an affected fetus.

Diagnosis

Clinical Diagnosis

The clinical diagnosis of Milroy disease is based on the presence of lower-limb swelling, present at birth or developing soon after, large-caliber veins, and upslanting, ‘ski-jump’ toenails. The swelling is usually but not always bilateral. In neonates the swelling predominantly affects the dorsum of the feet. With age the swelling may improve or progress to affect the whole lower leg.

Lymphoscintigraphy. Radioactive colloid is injected into the toe web spaces and uptake in the ilioinguinal nodes is measured at intervals. Lymphoscintigraphy is performed to determine if there is lack of uptake of radioactive tracer. This can help with the diagnosis of Milroy disease as other forms of lymphedema can have differing patterns on lymphoscintigraphy. In cases of unilateral swelling, lymphoscintigraphy can determine if lymphatic drainage is impaired in the 'unaffected' leg.

Note: (1) Lymphoscintigraphy normally replaces lymphangiography (x-ray after direct injection of dye into the lymphatic vessels in the foot) as it is less invasive. (2) Lymphangiography is also technically more problematic because of difficulties locating lymphatic vessels for cannulation.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. FLT4 (VEGFR3) is the only gene known to be associated with Milroy disease [Ferrell et al 1998, Irrthum et al 2000, Karkkainen et al 2000a, Evans et al 2003].

Other loci. No other loci have been identified, but reports suggest that Milroy disease is genetically heterogeneous [Holberg et al 2001, Evans et al 2003]. Even when the individual has a clear clinical diagnosis, an FLT4 mutation is found in only 75% of affected individuals, suggesting that other genes may be involved [Connell et al 2009].

Clinical testing

Sequence analysis. The mutation detection frequency using sequence analysis is currently unknown as limited data are available. Connell et al [2009] suggest that with rigorous phenotyping a detection rate of up to 75% can be expected in those clearly affected and with a positive family history. If those with typical Milroy features but without a family history are included the mutation pick-up rate is around 68%.

Testing Strategy

Confirming/establishing the diagnosis in a proband

Rigorous clinical phenotyping is essential.

Lymphoscintigraphy is not essential to make the diagnosis and one can proceed directly to molecular testing.

A family history makes it more likely that an FLT4 mutation will be found. In those with congenital lower-limb lymphedema but no family history, the pick-up rate is around 68% [Connell et al 2009].

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in FLT4.

Clinical Description

Natural History

The most common finding in Milroy disease is lower-limb lymphedema. The edema is usually present from birth. In neonates the swelling tends to affect primarily the dorsum of the feet. Anecdotal evidence suggests that on rare occasions it develops later in life.

The amount of edema varies both within and among families. Swelling is often bilateral, yet asymmetric.

The degree of edema sometimes progresses but in some instances can improve, particularly in early years.

Other features sometimes associated with Milroy disease include:

Hydrocele (37% of males)

Prominent veins (23%)

Upslanting toenails (14%)

Papillomatosis (10%)

Urethral abnormalities in males (4%)

Cellulitis occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females [Brice et al 2005]. Cellulitis can damage the existing lymphatic vessels, resulting in an increase in the degree of swelling.

Prenatal pleural effusion and chylous ascites have been reported rarely [Daniel-Spiegel et al 2005], but in general Milroy disease is not associated with more widespread lymphatic abnormalities.

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been reported.

Intra- and interfamilial variation in the phenotype is wide.

Natural History

The most common finding in Milroy disease is lower-limb lymphedema. The edema is usually present from birth. In neonates the swelling tends to affect primarily the dorsum of the feet. Anecdotal evidence suggests that on rare occasions it develops later in life.

The amount of edema varies both within and among families. Swelling is often bilateral, yet asymmetric.

The degree of edema sometimes progresses but in some instances can improve, particularly in early years.

Other features sometimes associated with Milroy disease include:

Hydrocele (37% of males)

Prominent veins (23%)

Upslanting toenails (14%)

Papillomatosis (10%)

Urethral abnormalities in males (4%)

Cellulitis occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females [Brice et al 2005]. Cellulitis can damage the existing lymphatic vessels, resulting in an increase in the degree of swelling.

Prenatal pleural effusion and chylous ascites have been reported rarely [Daniel-Spiegel et al 2005], but in general Milroy disease is not associated with more widespread lymphatic abnormalities.

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been reported.

Intra- and interfamilial variation in the phenotype is wide.

Milroy disease is suspected in individuals with 'woody' swelling of the dorsum of the feet with few associated features. Family history, if present, is consistent with autosomal dominant inheritance.

Gene Review - complete article

Milroy Disease

Milroy disease is a condition that affects the normal function of the lymphatic system. The lymphatic system produces and transports fluids and immune cells throughout the body. Abnormal transport and accumulation of lymph fluid can cause swelling (lymphedema). Individuals with Milroy disease usually develop lymphedema in their lower legs and feet soon after birth. The lymphedema typically occurs on both sides of the body and does not worsen over time. Milroy disease is associated with other features in addition to lymphedema. Males with Milroy disease are sometimes born with an accumulation of fluid in the scrotum (hydrocele) or abnormalities of the tube that carries urine from the bladder to the outside of the body (urethra). People of both genders may have upslanting toenails, deep creases in the toes, wart-like growths (papillomas), and prominent leg veins. Some individuals develop a non-contagious skin infection called cellulitis, which can damage the thin tubes that carry lymph fluid (lymphatic vessels). Cellulitis is more common in males than in females and causes further swelling in the lower limbs.

How common is Milroy disease?

Milroy disease is a rare disorder; its incidence is unknown.

What genes are related to Milroy disease?

Mutations in the FLT4 gene cause some cases of Milroy disease. The FLT4 gene provides instructions for producing a protein called vascular endothelial growth factor receptor 3 (VEGFR-3), which regulates the development and maintenance of the lymphatic system. Mutations in the FLT4 gene interfere with the growth, movement, and survival of lymphatic cells. These mutations lead to the development of small or absent lymphatic vessels. If lymph fluid is not properly transported, it builds up in the body's tissues and causes lymphedema. It is not known how mutations in the FLT4 gene lead to the other features of this disorder.

Many individuals with Milroy disease do not have a mutation in the FLT4 gene. In these individuals, the cause of the disorder is unknown.

How do people inherit Milroy disease?

Milroy disease is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In many cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the FLT4 gene. These cases occur in people with no history of the disorder in their family. About 10 percent to 15 percent of people with a mutation in the FLT4 gene do not develop the features of Milroy disease.

Genetics Home Reference

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