9th State of Georgia Lymphedema Education & Awareness Day

9th State of Georgia Lymphedema Education & Awareness Day

MARK YOUR CALENDERS!

Our conferences here in Georiga are absolutely fantastic and there is no charge. The only expenses you might have would be the lunch and/or lodging if you come from out of town.

Last year we had Dr. Kathleen Francis updating us on research. She was great...totally cool person too!!!! Here's the scoop on this years conference: 9th State Of Georgia Lymphedema Education & Awareness Day

Sponsored by

Lighthouse Lymphedema Network

Luncheon & Program

Saturday, October 28, 2006 9:00 a.m. - 3:00 p.m. at the Renaissance Waverly Hotel 2450 Galleria Parkway, NW - Atlanta, GA

Speaker: David N. Finegold, M.D.

Some topics to be discussed:

· The genetics of primary lymphedema
· Post-mastectomy secondary lymphedema
· The future of lymphatic research

Our sincere thanks to the following businesses for their financial support of this educational seminar.

Please stop by the tables and see the services and products provided by our supporters for the treatment of lymphedema and related conditions.

· A Woman's Place - Northside Hospital
· BSN-Jobst
· CircAid Medical Products
· Compass Healthcare, Inc.
· Compression Design
· Drapers Fitness & Rehab Consulting
· Gwinnett Medical Center
· Juzo · Medi, USA
· Peninsula Medical (The Reid Sleeve People)
· Sigvaris, Inc.
· Solaris, Inc. (Tribute/Swell Spots)

Be there or be square

Treatment of Pediatric Lymphedema

The Treatment of Pediatric Lymphedema

by Steve

Any discussion of pediatric lymphedema must include information about our most current scientific understanding of the underlying causes. Pediatric lymphedema may be uncomplicated in its presentation, akin to a benign adult primary lymphedema, or may indeed be very medically complex. One must assume in any pediatric form of lymphedema that there is either a defect in the normal development of lymphatic tissue, or that the visible swelling may be one of the first signs and symptoms of malignant disease. For this reason no condition involving edema should be casually viewed or dismissed by the medical professional and immediate clarification as to the presence or absence of cancer must be investigated.

Classification

The two main classifications of lymphedema are primary and secondary and are labeled as such according to the cause of the lymphatic impairment. Primary lymphedema can be described as an inherent defect within the lymphatic tissue itself. This malformation may involve either the absence of tissue or a malformation of tissue, (usually lymph vessels) which results in the presence of abnormally high levels of proteins and tissue fluids within the tissue spaces (interstitium). Secondary lymphedema is always associated with a traumatic event or series of events. Causes include multiple infections of the skin or soft tissues, surgical removal of lymph nodes, as in cancer treatment, radiation therapy, acute thrombo-phlebitis (DVT) or other traumas. Again the consequence is similar (lymphedema) and results in a disturbance of normal lymphatic drainage.

Following astute investigation and differential diagnosis, benign primary lymphedema (not associated with cancer) occurring in an infant at birth or within the first year of life is classified as Type 1 Nonne-Milroy Syndrome ( Milroy's Disease). This ''congenital hereditary'' (present at birth, sometimes inherited) form of lymphedema is described as usually involving the lower extremities but sometimes the arms, hands and face and may also be associated with malformations of the intestinal lymphatics (hyperplasia or other dysplasia). The additional intestinal involvement may result in poor absorption of proteins into the blood stream. This is due to congestion created by large fatty molecules that also rely upon lymphatic vessels for absorption. Symptoms may include bloating of the abdomen (ascites), low blood albumin levels (hypo-proteinemia), high protein levels in the stool (protein losing enteropathy) and in advanced cases, a malnourished appearance. Some Milroy's patients may require special dietary guidelines involving less complex fatty acids, which are often times successful in alleviating the congested intestinal lymphatic system.

Additional classifications of primary lymphedema occurring in children include Type 2 Meige Syndrome. This non-congenital familial (not present at birth, sometimes inherited) form is associated with the changes of puberty and mainly occurs in females. As in Milroy's disease this form is associated with lower extremity lymphedema, is chronic and progressive if left untreated, but does not involve intestinal lymphatic malformations. Both Type 1 and Type 2 primary lymphedema can further be classified as lymphedema praecox, which is an umbrella label used to describe any primary lymphedema occurring before the age of 35. Of the two types, type 1 (Milroy's Disease) accounts for 6-7% of all lymphedema praecox cases. (1)

Differentiation

Other diseases associated with pediatric lymphedema, which are beyond the scope of this article include Klipple Trenaunay Weber Syndrome (KTWS, otherwise termed Angio-Osteohypertrophy Syndrome), Noonan's Syndrome, Turner's Syndrome, Amniotic Band Syndrome (3 chromosomal disorders) and others. Of the aforementioned syndromes, KTWS is not uncommonly encountered in a busy lymphedema clinic and is a serious medical disorder involving overgrowth of veins, arteries, bones and lymphatic tissues. Practicing lymphedema therapists and diagnosing physicians must be able to identify this condition and make treatment adjustments to accommodate the complications of this disease. It is recommended that those pediatric patients with KTWS and associated lymphedema seek expert physician supervision, preferably from a vascular surgeon with additional training in lymphology.

Diagnosis

As previously mentioned, pediatric lymphedema may be ''pure'' (uncomplicated) or complicated by other associated disorders of the vascular system or may involve physical obstruction, as in the case of malignancy. For this reason it is imperative to seek expert physician assessment in all cases. The correct diagnosis is nearly always gained clinically however, and relies in large part upon skilled observation, palpation and historical analysis. One safe and minimally invasive imaging procedure currently used to diagnose primary lymphedema is called Lymphangioscintigraphy (LAS). This procedure involves subcutaneous (within the dermis) injections of radioisotope tracers, which are photographed at set intervals to show the amount and speed of uptake and transport within the individuals' lymphatic system. However, when primary lymphedema is accurately diagnosed clinically, LAS may be omitted, as it will not change the course of treatment. Clearly, LAS is of great academic value and more importantly, may contribute to supporting the accuracy of the clinical diagnosis. Many times, as in the case of pediatric lymphedema, a clear image of the insufficient lymphatic drainage may put to rest parental concerns that lymphedema is not the only disease process at work.

Other testing procedures such venography and lymphography, which involve injections of dye are both painful and potentially damaging to vessel structures and have also been associated with deadly allergic reactions (anaphylaxis). In more complicated cases involving combination forms of lymphedema, Magnetic Resonance Imaging (MRI), Computer Tomography (CT scan) and Venous Doppler studies may be required to assist in designing a successful treatment plan. In uncomplicated cases, they are not necessary and only incur additional expense.

Treatment

At present there is no cure for lymphedema. It is unfortunate that surgical interventions are still sometimes undertaken as a form as treatment for all types of lymphedema. Although many brilliant and well-intentioned surgeons have attempted a myriad of ingenious techniques, it remains a fact that no reliable benefits have come from these procedures. More often surgery results in significant additional cosmetic disfigurement or lymphatic impairment. The most common type of surgery can be categorized as a ''debulking procedure.'' It is not logical to believe that the removal of substantial amounts of subcutaneous tissue, containing functional lymphatic vessels, will result in an improvement of the overall condition. Surgery is therefore not indicated for extremity lymphedema.

Another common treatment for lymphedema is the pneumatic compression pump. Although pumps provide some relief and may temporarily halt the advancement of swelling, the benefits are nearly always temporary and may result in abnormally large accumulations of lymph at the root of the limbs and within the trunk. Significant numbers of patients with lower extremity lymphedema who have been treated by pumps report genital lymphedema following daily use (2). This consequence is nearly always avoided by comprehensive treatment with Complete Decongestive Therapy (CDT).

Complete Decongestive Therapy (CDT)

When the condition is present during infancy parents can benefit their child greatly by implementing a course of conservative treatment as early as possible. By initiating a sensible treatment strategy early on, it is hoped that the chronic and progressive consequences of the disease can be significantly lessened. The treatment method universally accepted as the gold standard of care for lymphedema is called Complete Decongestive Therapy (3). This program of treatment relies upon four interdependent components and is successful in halting the progression of the swelling, the chronic inflammatory changes within the skin (lymphostatic fibrosis) and promotes healthier immune response in the affected areas (4).

Additionally, CDT liberates the patient from encumbrances such as pneumatic compression pumps or limb elevation, and requires healthful activity levels and proactive patient involvement. The four components of CDT are: Manual Lymph Drainage (MLD), compression bandaging, remedial exercise and infection prevention (meticulous skin and nail care). Self-care training involving any of these components with the goal of optimizing the clinical treatment results in homecare should be seen as an important additional component.

CDT Guidelines for Pediatric Patients It has been the authors' experience that typical approaches to treatment must be significantly modified for the pediatric patient, especially in the case of infantile lymphedema. The following suggestions are the result of clinical experiences gathered through treatments involving dozens of children.

All parents of children with lymphedema must be educated about the condition so that a realistic picture of this chronic condition can be gained. No surgical cure or pharmaceutical medication is available. It is unfortunate that lymphedema is presently an incurable condition, however, with early competent guidance the secondary tissue changes associated with lymphedema can be greatly reduced. Overall limb size can be maintained at nearly normal girth and immune function can be enhanced with ongoing Manual Lymph Drainage treatments. These benefits cannot be underestimated, because the long-term impact is quite positive and rewarding. Normal limb function and socialization can be expected in most cases. Children with lymphedema can live very normal lives.

Be patient with the process

Overly aggressive care is never productive for the adult or child with lymphedema. Especially in pediatric cases where all tissues are delicate, great care must be taken to avoid creating injury or discomfort. One must remember that a comfortable and happy patient will be a compliant patient. This special child must not be mishandled. Parents can be ''consumed with worry'' and approach compression bandaging overzealously, with the mistaken impression that ''more pressure is better''. It is more likely however to produce discomfort, pain or skin infections which can actually cause a worsening in the condition. Pediatric patients cannot tell us what is bothering them early on, and without this feedback the caregiver must adopt a relaxed and careful approach to compression therapy.

Similarly, the Manual Lymph Drainage (MLD) treatments delivered by the parent may be counterproductive if they are heavy handed or rough. Lymphatic vessels are delicate, threadlike structures, which may spasm or become otherwise injured by inappropriate treatment. In the clinic, parents must invest time into learning the appropriate skills. This investment cannot be underestimated in its importance and also allows for question and answer sessions between parent and therapist. The better educated the parent the more likely they will be to provide high quality care for their child.

Depending upon the age of the child, most will initially need to adjust to this ''strange new routine'' as well as to the intervening therapist. Time must be budgeted for this necessary process to take place and may require ''play sessions'' at first to create a feeling of comfort and safety. Suggestions include setting up a television and video player in the treatment room as a distraction; bring favorite toys, music and foods. Place a soft clean quilt on the floor and attempt treatment and bandaging from this vantage point. Allow the parent to hold the child on his/ her lap while the therapist works. All the while verbal education can take place between therapist and patient, which is usually of great value. At first this format may seem unproductive and can be a source of further anxiety for the parent, however, should this step be omitted, the young child will not comply with any of the components of the program and will ultimately create an even less productive outcome. This approach may also allow for a more ''semi-intensive'' approach, in that the total treatment duration is reduced to 2 weeks versus 4+ weeks as in the case of an adult. Treatments can therefore be budgeted for future use involving frequent follow up visits where parent, patient and therapist can review home care techniques and remain current concerning the overall condition of the child.

Start with MLD and self-care suggestions

For the very young child of less than one year of age, therapists may be quite productive in administering MLD. This ''massage like'' treatment involving gentle, soothing skin manipulation is usually well received by the infant. Parents can observe and repeat the agreed upon treatment sequences at home and may find that the best time to administer treatment is during nap times or at night while the child is sound asleep. Older children of age 18 months to 3 years who are considerably more active and less agreeable to this routine may also benefit from similar timing. The quality of touch required for proper MLD treatment is so gentle that children will become positively conditioned, and in time will view it as another form of loving touch from the parent and therapist. They will also be able to develop skills for their self- care and can be engaged in practice as they mature.

The goals of MLD are to create more efficient drainage within the affected area and systemically offset the chronic skin changes associated with lymphedema. In children the early intervention of MLD is extremely valuable in slowing or reversing these effects especially on the dorsum of the hand and fingers and similarly on the dorsum of the foot and toes. In some cases the genital area is also chronically involved, MLD application is essential and may again, offset chronic skin changes.

Compression Therapy Considerations

As previously mentioned, pediatric tissues are far more delicate than those found in an adult. Compression therapy can be counterproductive if it is not administered with great care and skill. This becomes an additional burden to parents and must only be undertaken by responsible and cautious caregivers.

It has been the authors experience that some patients are simply too young to intervene with compression therapy. However, the skilled therapist may provide a modified bandage in the clinic to gain a clearer picture of the potential for improvement. This bandage may not be practical for parental application until a later date. A very young infant (1-4 months old) will benefit from the stimulation of MLD alone and, as the child begins to stand, gravity becomes an exacerbating factor, necessitating external support in the form of compression bandaging and/ or medically correct compression garments. The only situation where intensive compression bandaging would be provided before this time is in the case of massive swelling (elephantiasis), a situation rarely encountered in infants.

Once the child begins to stand, lymphedema of the legs and feet may begin to worsen. This is the point in time where some compression strategies should be explored and employed. Therapist and parent must consider the benefits and tradeoffs carefully however, as bulky, multi-layered bandaging may impact the child's ability to safely ''toddle''. Bending the knees to crawl is made more difficult, and in the case of arm lymphedema, tactile skills and simple grasping tasks may be largely compromised. For these reasons and including the child's tolerance level, an intensive phase of 2 weeks (10+ treatments) is usually adequate to deliver quality care, and homecare education to astute parents. Within this time frame the therapists goals should include: Achieving a fair amount of reduction (without force), learning the unique compression gradient for optimal long-term improvement, effectively educating one or more caregivers in basic tailored MLD techniques, applying compression bandages safely, and measuring for any necessary compression garments.

Special Compression Guidelines

Most bandaging materials are sized for the adult frame and are too large for most young children and especially the infant patient. Select 4cm compressions bandaging materials such as DemaBand® in these cases and graduate to 6cm Comprilan/Rosidal®, or at the maximum, 8cm materials for most children. Another special product that is kind to pediatric skin is Velfoam®. This fleece-lined foam padding material is quite kind to delicate tissues and should be incorporated or substituted for other forms of padding. Artiflex®, and Cellona® synthetic cotton padding products can also be used in combination with foam but should not be exclusively applied otherwise shifting will occur. Toes are usually too tiny to affectively wrap. A tourniquet effect is more likely on small circumferences and great caution should be used if an attempt is made. It is the authors' opinion that gentles MLD and manual manipulation can affectively treat toes. Fingers may be wrapped with traditional materials such as Transelast® or Elastomull® of an appropriate width. Take care to double the bandage into two-ply as it will concentrate the bandage on a smaller skin area

.Compression garments are usually fitted to age appropriate patients (12+ months). The benefit of these elastic sleeves is that they provide medically correct gradient pressure. By wearing a sleeve and glove or leg stocking daily, pediatric patients will experience liberation from cumbersome bandages. Normal developmental milestones can be reached without delay such as coordinated walking. Furthermore, since bandaging is practiced at night, parents can rest assured that less than expert-bandaging technique can be corrected by daytime gradient compression.

Activity and Lifestyle

Due to the chronic and lifelong nature of lymphedema, parents are encouraged to permit their child to engage in normal activities such as sports, arts and crafts, and outdoor play. With lymphedema comes an increased risk of acute infection (cellulites) especially when the skin is injured. However, to disallow normal play may have significant and more troubling side effects that may be mental or emotional in nature. Furthermore, many lymphedema patients have no history of infection following numerous traumas and are therefore capable of normal activity. If infections are an occurrence, some activities should be modified accordingly but with an awareness of these larger concerns. Lymphedema in the majority of cases is not a disabling condition, however children who have been raised to feel as though they have a disability are truly at a disadvantage and may not experience the joy and freedom of childhood that is their birthright.

See Also:

Children with Lymphedema - Yahoo Support Group

Children's and Pediatric Lymphedema

National Lymphedema Network - Parents' Lymphedema Action Network

Putting the Squeeze on Lymphedema

Putting the Squeeze on Lymphedema

Nursing Made Incredibly Easy!March/April 2006 Volume 4 Number 2Pages26 - 342006 Lippincott Williams & Wilkins, Inc. Volume 4(2), March/April2006, p 26-34

HOLCOMB, SUSAN SIMMONS ARNP, BC, PhD

Nurse Practitioner, Olathe Health System, Inc., Olathe,Kan.Consultant, Continuing Nursing Education, Kansas City, KansasCommunity College, Kansas City, Kan.

The author has disclosed that she has no significantrelationships with or financial interest in any commercial companiesthat pertain to this educational activity.

Abstract

When a portion of the lymphatic circulation develops abnormally orisinjured by trauma, surgery, or radiation therapy, fluid balance isthrown off kilter and the patient can experience severe swelling inanextremity. In this article, we'll help you learn about the differenttypes and stages of lymphedema and the treatment options for thisdifficult condition. We'll also offer you advice on preventionstrategies and patient teaching.

MOST OF US are familiar with lymphedema following breast cancertherapy, especially when axillary dissection and axillary radiationtherapy are used. Slightly more than a quarter of patients whoreceive treatment for breast cancer are affected by lymphedema, andit can cause substantial functional and psychological impairment.

Of course, cancer treatment isn't the only cause of lymphedema. Inthis article, I'll help you understand the types of lymphedema, itscauses, possible complications, and preventive and treatmentstrategies.

Let's start off with the causes and a description of the varioustypes of lymphedema.

A blockage in the flow

Lymphedema is the result of excess proteins, fluid, inflammation, and fibrosis in the lymphatic system. It's divided into two types: primary and secondary, based on the underlying cause.

Primary lymphedema affects anywhere from 1 to 2 million individuals in the United States. It's twice as common in women as in men, and it affects the lower extremities three times more often than the upper extremities. It's bilateral in two-thirds of cases. Primary lymphedema isn't a progressive disease.

Congenital lymphedema

Congenital lymphedema is typically characterized by absence or abnormality of the lymphatic tissue; it's clinically evident at birth. Milroy disease, a kind of congenital lymphedema, accounts for about 2% of all primary lymphedema cases.

Lymphedema praecox , which expresses itself between birth and 35 years of age, is the most common type of inherited primary lymphedema, accounting for 65% to 80% of all cases of primary lymphedema.
Lymphedema tarda , also known as Meige disease, has a late onset; it usually doesn't appear until after age 35. It's the rarest form of primary lymphedema.lymphedema praecox , and lymphedema tarda are forms of primary disease distinguished by the age of onset.

Secondary lymphedema , the kind most of us are familiar with, is an acquired condition. It's usually caused by an obstruction or trauma to the lymphatic system that interferes with lymphatic flow. In the United States, it's most commonly caused by injury to or removal of regional lymph nodes during surgery or radiation therapy, infection, or tumor growth. Secondary lymphedema affects between 2 and 3 million individuals in the United States. Worldwide, the most common cause of secondary lymphedema is filariasis, an infestation of the lymph nodes by the parasite Wuchereria bancrofti ; it's this organism that gives rise to elephantiasis.

No Way Out

The lymphatic system is made up of lymph vessels, tissue, and organs. Lymphocytes, a specialized type of white blood cell, circulate throughout the lymphatic system to help the body fight off disease and infection. Lymph vessels collect a fluid that's made up of protein, water, fats, and wastes from the cells of the body and then carry the fluid to the lymph nodes. Lymph nodes filter out potentially harmful waste and foreign materials. Lymph vessel walls are thinner than those of venous and arterial blood vessels, allowing larger proteins to permeate the vessel walls.

If excessive amounts of protein and fluid overload the lymphatic system, they begin to accumulate in the interstitial spaces. Lymphedema is distinct from other forms of edema in that material trapped in the interstitial spaces has a higher concentration of protein.

The protein and fluid in the interstitial spaces prompt an inflammatory response. Fibroblasts migrate to the area and deposit collagen. This changes the initial pitting edema into the brawny (orange), nonpitting edema characteristic of lymphedema. Pitting refers to the indentation that persists when a finger is pressed into an edematous area. See It's the pits for the International Society of Lymphology's staging system.

We'll look next at the clinical presentation of secondary lymphedema.

Secondary Lymphedema - keep it up

Secondary lymphedema can occur acutely, or it may have a more insidious, gradual onset. Four patterns of acute lymphedema are recognized:

Mild acute lymphedema lasts for only a few days. It usually occurs following surgery to remove a lymph node or after an injury to lymphatic vessels that occurs during surgery. This form of acute lymphedema may be recognized by a warm, erythematous, and nonpainful limb associated with the lymphatic chain near the area.Treatment includes elevating the affected extremity and contracting the muscles of the extremity to enhance blood flow and, consequently, lymphatic flow back to the heart.

The second type of acute lymphedema occurs 6 to 8 weeks after surgery or radiation to the affected area. It's noted by a warm to hot, erythematous, very tender limb.To treat it, the affected limb is elevated and anti-inflammatory medications are given to reduce inflammation of the lymphatic vessels and/or veins.

The third type of acute lymphedema affects the superficial lymphatic vessels and nodes following an insect bite or other minor injury in the area. The affected area's signs and symptoms are very similar to the second type of acute lymphedema in that the area is painful, warm to hot, and erythematous. Edema may also be apparent. The affected limb is elevated, and because the risk of infection is increased, antibiotic prophylaxis is given.

*** Editor's note - clinical studies actually indicate that secondary lymphedema may lie latent for years until it is "triggered" by an event that overwhelms the lymph system. ***

The fourth and most common type of acute lymphedema develops 18 to 24 months following cancer surgery, although in some cases, it may take years to develop. Pain is the hallmark symptom of the fourth type of acute lymphedema. It's typically felt in the neck, shoulders, back, and hips.This type of acute lymphedema is more complicated to treat because the painful affected areas tend not to be in an extremity, making elevation tricky. Pain medications and/or anti-inflammatory agents may help.Acute lymphedema generally resolves within 6 months. Factors that could cause acute lymphedema to become chronic include a surgical drain leaking protein into the surgical site, inflammation, paralysis of the affected limb, loss of lymphatic function in the area, and/or blockage of a vein by a blood clot or inflammation.In chronic lymphedema, the lymphatic flow can't meet the demands made on it. Many of the problems that cause acute lymphedema also contribute to chronic lymphedema. Unlike acute lymphedema, however, chronic lymphedema isn't reversible. Treatment is palliative, not curative. Pain, heat, edema, and erythema are also characteristic of chronic lymphedema. Elevation of the affected extremity doesn't help edema in chronic lymphedema, and the skin eventually becomes hardened or fibrotic.

Let's move on next to diagnosis and treatment of secondary lymphedema.

Nailing the diagnosis

Unlike patients with arterial or venous disease, most patients with lymphedema don't report symptoms other than those related to the weight and size of the limb. Oozing fluids may cause pruritus.

Your patient assessment must include a history and physical exam. Make sure you ask about past surgery, postoperative complications, radiation treatment, and how long it was between the time of surgery or radiation and the onset of lymphedema. You should assess the quality and behavior of the edema: Does it change with position? Has it progressed over time? Find out if there's a history of trauma or infection, and be sure you get the whole scoop on current medications.

No specific tests are used to diagnose lymphedema. Diagnosis is generally made on clinical presentation and history. Edema usually isn't detectable clinically until the interstitial volume is about 30% above normal.

Occasionally, imaging studies may be helpful to assess lymphatic flow or to identify tumors. The most commonly used noninvasive techniques are lymphoscintigraphy, computed tomography scans, and Doppler ultrasonography. In lymphoscintigraphy, a water-based radionuclide is injected into the lymphatic tissues, allowing the dynamics of the flow to be traced, any reversal of flow to be identified, and the severity of the obstruction to be determined.

If there are any lingering doubts over a diagnosis of lymphedema, a chemical evaluation of the protein content of the edema fluid should put them to rest. A tissue fluid analysis with a protein content between 1 and 5.5 g/dl usually indicates lymphedema; 0.1 to 0.9 g/dl is more indicative of venous or cardiac edema.

Better sooner than later

The main focus of treatment for secondary lymphedema lies in prevention. Lifestyle plays an important role, and patients should be encouraged to consume a healthy diet, maintain a normal body weight, and participate in regular exercise. Patients with lymphedema need to take particular care not to do anything that could lead to infection. Even a minor scratch to the skin near the area may become infected. The National Lymphedema Network, a nonprofit organization, offers an excellent guideline for risk reduction. See also Educating patients about lymphedema for more information.

The good news is that tissue loss or ulceration related to lymphatic obstruction with subsequent lymphedema is unusual. Tissue loss occurs because of a concurrent secondary pathology. As already noted, patients with lymphatic obstruction are prone to infections in the affected extremity caused by bacteria or, more commonly, fungus. As part of your assessment, you should examine intertriginous folds for ulcers and areas of infection. Explain to your patients that this is important to do at home too. It may be helpful to show them how to use a mirror to visually examine those hard-to-see nooks and crannies.

To be effective, lymphedema treatment must improve lymph flow and drainage. The best outcomes are obtained when therapy begins before irreversible sclerotic changes occur in the interstitium. Strict adherence to therapy is essential and lifelong.

Let's take a closer look at the types of lymphedema treatments.

Complete decongestive therapy (CDT) has four stages

Manual lymph drainage (MLD) is a gentle manual treatment administered by a trained therapist. MLD reroutes lymph flow around the blocked area into more centrally situated, healthy lymph vessels. From there, the flow can drain into the venous system. Special massage techniques help to break down fibrotic tissue to restore flow.

With compression bandaging , slightly elastic cotton bandages are wrapped around the affected extremity to increase tissue pressure, helping to push the excess fluid and protein out of the area. Compression bandaging also helps keep more fluid and protein from flowing in and breaks down areas of scarring and fibrosis. Note that compression-bandage therapy for lymphedema requires the application of more pressure than compression-bandage therapy for venous disease: about 30 to 40 mm Hg for venous disease versus about 50 to 60 mm Hg for lymphedema.

Remedial exercises are performed with compression bandages or compression garments in place. Breathing exercises help to increase the volume of lymph fluid carried through the thoracic duct (the body's largest lymph vessel).

Remedial exercises increase lymph vessel activity and improve lymph circulation.
Meticulous skin and nail care reduces bacterial and fungal growth, which decreases the risk of infection.

Contraindications for CDT and MLD include acute infection, cardiac edema, malignant disease, and pulmonary edema from chronic obstructive pulmonary disease.

*** Editor's note - new studies indicate that infact complete decongestive therapy does NOT cause cancer to spread and that it may be totally safe for cancer patients to continue this treatment. More research is being done to confirm this. ***

Get out and stay out

Once the excess protein and fluid are reduced and the extremity is at its smallest possible size, the goal is to keep the edema from coming back. Many patients find that daily wrapping and unwrapping of bandages is awkward and time-consuming, so carefully explain to them why the bandaging is necessary. Various commercially available binding garments can be helpful alternatives to bandaging. One note of caution, however: Whether a bandage or garment is used, it must be applied correctly; improper application can compress nerves or blood vessels, which can cause complications.

Arterial disease is a contraindication for the use of compression bandages or garments. Caution should also be used in patients with hypertension, paralysis, diabetes, asthma, and heart failure.

Specialized lymphatic drainage pumps, called gradient pneumatic lymphedema pumps or intermittent pneumatic compression pumps, are also available. The extremity or part of the extremity, such as the foot, is wrapped, and the pump applies gradient pressure with more pressure on the distal end than on the proximal end. The pump also provides sequential pressure, a technique like milking that pushes the fluid from the distal end of the extremity toward the trunk and central body cavity.

*** Editor's note - compression pumps have clinically been proven safe and effective for arm lymphedema. For lower limb lymphedema (leg lymphedema) there remains too great of a risk of genital lymphedema and damage to the cutaneous lymphatics to be a recommended treatment. See also: Why Compression Pumps Cause Complications with Lymphedema *** .

Water pills don't work

There's not much available in the way of effective medical therapy for lymphedema. Diuretics have little or no value. They draw off the excess water in the interstitial spaces, but not the excess protein. As soon as the diuretic is stopped, the concentrated proteins pull more water back into the affected area.

The dietary supplement coumarin, a benzopyrone, isn't approved in the United States and may produce serious adverse effects, in particular, liver toxicity. Selenium therapy for secondary lymphedema of the arm caused by breast cancer surgery is currently under investigation in a clinical trial. The theory behind the selenium trial is that the damage to the lymphatic system is linked to excessive generation of oxygen radicals; the researchers hypothesize that selenium, an antioxidant that gobbles up oxygen radicals, might decrease the damage to the lymph system.

Also under investigation in a clinical trial is the use of hyperbaric (high-pressure) oxygen therapy for the treatment of secondary lymphedema caused by breast cancer treatment. According to the National Institutes of Health ), the researchers think that hyperbaric oxygen may stimulate the growth of new lymphatic channels as well as lead to a reduction in scar tissues surrounding existing lymphatic channels in the armpit.

***Editor's note: see Complications of Lymphedema Debulking Surgeries***

Occasionally, surgery is used as a palliative treatment to relieve pressure and edema. It's usually considered the treatment of last resort to relieve otherwise intractable pain.

Complications associated with lymphedema are, in general, associated with an infection in the affected limb. If the pelvic lymphatic system is affected, problems of elimination may occur.

A rare and lethal complication is lymphangiosarcoma, cancer of the lymphatic vessels; it can develop after the patient has had chronic lymphedema for 10 years or more. The incidence is estimated to be 0.45% in patients who survive at least 5 years after radical mastectomy; a lower incidence of 0.07% is seen in patients after simple mastectomy. Death from lymphangiosarcoma generally occurs within 18 months, with the 5-year survival rate at around 10%.

Physical findings of lymphangiosarcoma are bluish-red or purplish bumps on the affected extremity that resemble slightly raised ecchymosis. The tumors are very aggressive and characteristically metastasize early to multiple sites, most often to the lungs. Treatment may involve amputation of the affected extremity or wide local excision of the lesions. Lymphangiosarcoma that arises following mastectomy is called Stewart-Treves syndrome.

Let's finish up with a discussion of some ways to keep your patient with lymphedema from getting worse or running into complications.

At home

Stress to all patients with lymphedema the importance of reporting any signs and symptoms of infection in the affected extremity to the primary care provider.

Patients should also be given nutritional guidance to help them maintain adequate protein balance to help fight off infection. In general, the diet should provide 30 to 35 calories/kg/day, including 1.25 to 2 g protein/kg/day. Most patients can benefit from taking a daily multivitamin with minerals.

Lymphedema is disfiguring, sometimes painful, disabling, and often leads to big changes in a patient's lifestyle. These factors can all lead to depression. Support groups, counseling, and antidepressant medications may be useful for treating emotional disorders associated with a diagnosis of lymphedema (see Thanks for your support ).

Keep in mind that early recognition and appropriate treatment can help minimize progression and complications of lymphedema. It's your responsibility to help patients recognize lymphedema, avail themselves of appropriate interventions, and help them maintain a good quality of life.

It's the pits

The International Society of Lymphology has set the following staging system:

* Stage 0 -Subclinical condition where swelling isn't evident despite impaired lymph transport. It may exist for months or years before edema occurs.

* Stage I - Pitting may occur and is reversible. It may take up to a few hours of rest and elevation to reverse.

* Stage II -Pitting occurs, and the edema isn't appreciably reduced with elevation of the affected limb. In late Stage II, the tissue hardens and becomes fibrotic, and pitting no longer occurs.

* Stage III -This stage is also referred to as elephantiasis. Pitting is absent. Skin changes like acanthosis, fat deposits, and warty overgrowths may develop. Fluid may ooze from the skin due to high pressure in the lymphatic and venous vessels. It most commonly occurs in the legs and results from long-standing, inadequately treated or untreated lymphedema.

Did you know

The following conditions can mimic signs and symptoms of lymphedema:* allergic disorders* heart failure * hepatic cirrhosis* hereditary angioedema* hypoproteinemia* idiopathic cyclic edema* kidney failure* lipidemia* postphlebitic syndrome* total body excess of free water* venous disease.

Educating patients about Lymphedema

General measures* Elevate the affected arm or leg above your heart as much as possible.* Avoid having blood drawn or injections given in the affected arm, and avoid injections into the hip on the side of the affected leg.* Don't have your blood pressure measured on the affected arm.* If your legs are affected, don't sit for more than 30 minutes before getting up for a break. Also, don't cross your legs when sitting.* Avoid tight clothing and jewelry.* Don't hold or wear a purse on the affected arm.* Don't use ice packs or heating pads on the arm or leg that has lymphedema.* Don't use the affected limb to test the temperature of water. Feelings of touch, temperature, and pain may be reduced in the affected leg or arm.* Follow the diet and exercise plan developed by your health care team.* Keep your medical appointments.Prevent infection* Keep the affected arm or leg clean and dry; apply moisturizer often.* Use gloves and wear shoes when gardening.* Cut nails straight across, and don't cut your cuticles. Do not bite your nails or fingers. See a podiatrist or primary care provider if a nail infection or an ingrown nail occurs.* Use an electric razor for shaving.* Use an antibacterial ointment on cuts and scrapes.* Use gauze, not tape bandages, to cover cuts or scrapes.Prevent inflammation* Avoid injury to the affected arm or leg.* Avoid physical exercise or activities that might lead to cuts or bruises.* Always wear socks and shoes, especially outdoors.* Use extreme care and use protective devices on hands when using needles, knives, scissors, or other sharp objects if you have an affected arm.* Avoid getting sunburned; use sunscreen with an SPF of 30 or greater.When to call your primary care provider* You have signs and symptoms of infection like redness, pain, heat, swelling, and fever.* You notice a rash.* Your affected limb suddenly gets larger.

Source:

National Lymphedema Network

The National Lymphedema Network (NLN)

The National Lymphedema Network (NLN) is an internationally recognized non-profit organization founded in 1988 to provide education and guidance to lymphedema patients, health care professionals and the general public by disseminating information on the prevention and management of primary and secondary lymphedema. The NLN is supported by tax-deductible donations and is a driving force behind the movement in the U.S. to standardize quality treatment for lymphedema patients nationwide. In addition, the NLN supports research into the causes and possible alternative treatments for this often incapacitating, long-neglected condition.

National Lymphedema Network

I also want to let everyone know that today the National Lymphedema Network posted is new position paper of treatment for lymphedema.

You can find it at this link:

Lymphedema Treatment

Links to All their position papers from 2003-2006 can be found at this page:

National Lymphedema Network Position Papers on Lymphedema

These papers include:

Training of Lymphedema Therapists

Air Travel and Lymphedema

Exercise for Lymphedema Patients

Lymphedema Risk Reduction Practices

You can't get better information then what the NLN puts out.

Enjoy

Pat

Milroy disease and the VEGFR-3 mutation phenotype

Milroy disease and the VEGFR-3 mutation phenotype

Journal of Medical Genetics 2005

G Brice1, A H Child2, A Evans2, R Bell1, S Mansour1, K Burnand3, M Sarfarazi4, S Jeffery1 and P Mortimer5
1 SW Thames Regional Genetics Unit, St George’s Hospital Medical School, London, UK2 Department of Cardiological Sciences, St George’s Hospital Medical School, London, UK3 Department of Academic Surgery, St Thomas Hospital, London, UK4 Molecular Ophthalmic Genetics Laboratory, University of Connecticut Health Center, Farmington, CT, USA5 Department of Cardiac and Vascular Sciences (Dermatology), St George’s Hospital Medical School, London, UK

Correspondence to: Glen Brice SW Thames Regional Genetics Unit, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK; gbrice@sghms.ac.uk

Revised version received 15 September 2004Accepted for publication 18 September 2004

Abstract

Primary congenital lymphoedema (Milroy disease) is a rare autosomal dominant condition for which a major causative gene defect has recently been determined. Mutations in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene have now been described in 13 families world-wide. This is a review of the condition based on the clinical findings in 71 subjects from 10 families. All 71 individuals have a mutation in VEGFR-3. Ninety per cent of the 71 individuals carrying a VEGFR-3 mutation showed signs of oedema, which was confined in all cases to the lower limbs. In all but two cases onset of swelling was from birth. Other symptoms and signs included cellulitis (20%), large calibre leg veins (23%), papillomatosis (10%), and upslanting toenails (10%). In males, hydrocoele was the next most common finding after oedema (37%). Thorough clinical examination of these patients indicates that there are few clinical signs in addition to lower limb oedema. Rigorous phenotyping of patients produces a high yield of VEGFR-3 mutations.

Abbreviations: VEGFR-3, vascular endothelial growth factor receptor 3

Keywords: hydrocoele; lymphoedema; Milroy disease; VEGFR-3

In 1892 William Milroy described a family with congenital onset lymphoedema which was heritable, painless, non-progressive, and confined to the lower limbs.1 In his paper Milroy described a family consisting of 97 members, of whom 26, in six generations, had oedema. Some 35 years later Milroy attempted to follow up this family and was successful in locating 36 additional descendants.2

In William Osler’s, The principles and practice of medicine, lymphoedema was first designated with Milroy’s name.3 The lack of understanding of the cause of the condition is highlighted by the placing of the condition in the subsection of "Angioneurotic oedema" in the chapter entitled "Diseases of the nervous system". In his follow up paper of 1928, however, Milroy suggested that lymphatic blockage may be the underlying cause, but did not dismiss the idea of a vasomotor abnormality.

Primary lymphoedema is chronic tissue swelling, most commonly present in a lower limb, resulting from an intrinsic abnormality of lymph drainage.4 The term Milroy disease has unfortunately been increasingly used as a blanket term for all types of primary lymphoedema, whether or not the phenotype conforms to the original description by Milroy. Indeed Milroy himself did not clearly recognise that the type of lymphoedema he described was of a different aetiology to that described in 1898 by Henry Meige.5 Meige’s family differed in that his cases had onset of oedema at puberty and a description of what appears to be acute cellulitis was given.

With the advent of molecular medicine the underlying cause of at least three types of dominantly inherited lymphoedema has been elucidated. Ferrell et al6 and Evans et al7 published evidence for a gene locus for congenital familial lymphoedema (Milroy disease) at chromosomal location 5q35. The gene mutated at this position was found to code for vascular endothelial growth factor receptor 3 (VEGFR-3), a member of the tyrosine kinase receptor family.8,9 This receptor, activated by VEGF-C and VEGF-D, is required for lymphatic development during embryogenesis.10 All mutations found to date have been located in either of the two intracellular kinase domains and are presumed to interfere with tyrosine kinase activation.8,9
Mutations in the transcription factor gene, FOXC2, have been described in lymphoedema-distichiasis syndrome.11,12 In this condition the onset of oedema is usually at or after puberty. In addition to oedema, individuals with this condition often have distichiasis (aberrant eyelashes growing from the meibomian glands). The extra lashes are frequently the presenting complaint in this condition as their development precedes the oedema. A recent study has found an increased incidence of ptosis, varicose veins, cleft palate, and congenital heart disease amongst mutation carriers.13

More recently, mutations in the SOX18 gene have been reported to cause hypotrichosis-telangiectasia-lymphoedema syndrome.14 The mutations in this gene are associated with a very distinct phenotype—hypotrichosis and lymphoedema presenting in childhood and telangiectasia or vascular naevi, particularly on the palms and soles. To date there have been no studies looking for mutations in SOX18 in patients with isolated primary lymphoedema.

However, most families with lymphoedema do not have changes within the genes discovered thus far, indicating that there are several more genes for lymphoedema to be discovered. Further evidence for genetic heterogeneity comes from studies of lymphoedema families in which the results are not consistent with linkage to either the VEGFR-3 or FOXC2 loci.15

Thirteen mutations have now been located in VEGFR-3 in families with primary congenital lymphoedema8,9,16 although to date the detailed clinical phenotype of some of these families has been lacking. In this paper we describe the clinical phenotype of 71 patients from 10 families. All patients have mutations in one of the kinase domains of the VEGFR-3 gene.16

Methods

Patient ascertainment
Twelve families were originally ascertained on the basis of a family history of congenital lymphoedema. Seven probands were ascertained following referral to local lymphoedema clinics. Of the remaining five, two were referred by interested physicians and three, including two from the USA, self referred. All other family members subsequently enrolled in the study were contacted via the proband in the first instance. Two of the 12 families were excluded from this study as no VEGFR-3 mutation was identified although their clinical features were consistent with a diagnosis of Milroy disease.

Clinical phenotyping
In total, 211 individuals from the 10 families were clinically examined by at least one of the authors (GB, AHC, PSM, SM). Features of particular relevance included lymphoedema, venous abnormalities, and facial dysmorphism. Characteristic skin and nail changes, such as hyperkeratosis, skin thickening, increased skin markings, and fungal infections were also sought. Patients were questioned regarding their past medical history, family medical history, occurrence of cellulitis, venous problems, treatments, age at onset of swelling, and progression of the oedema over time. Care was taken to specifically exclude syndromes with a known genetic cause such as lymphoedema-distichiasis syndrome, hypotrichosis-lymphoedema-telangiectasia syndrome, and Turner and Noonan syndromes.

Molecular diagnosis
Initially, 12 affected probands with family histories of congenital lymphoedema were screened, looking for mutations in the VEGFR-3 gene. The results in all 12 families were consistent with linkage to chromosome 5q35. In 10 families, the entire gene was sequenced and eight mutations found. In the remaining two families, in which mutations were found, only the kinase domains were studied. Following discovery of a putative mutation in the proband, samples from all available affected and unaffected family members were analysed to ensure segregation of the sequence change with the affected phenotype.

Lymphography/lymphoscintigraphy
Ten patients (from five families) had previously undergone isotope lymphography (lymphoscintigraphy) or traditional x ray lymphangiography. Results of gamma camera isotopic scans were based on the images obtained and comparing the uptake of radioactivity in regional lymph glands relative to the injected dose in the foot.17

Results

Number M/F

Total patients with VEGFR-3 mutations 71 35/36
Lymphoedema present 64/71 (90%) 31/33
Age of Onset of Oedema
Congenital 62/64 (97%) 31/31
Non-congenital 2/64 (3%) 1/1
Extent of Oedema
Below Knee 60/64/ (94%) 28/32
Above Knee 4/64 (6%) 3/1
Bilateral Oedema 55/64 (85%) 26/29
Symmetry of oedema
Symmetrical swelling 35/64 (55%) 14/21
Right>left 15/64 (23%) 11/4
Left>right 5/64 (8%) 1/4
Unilateral swelling
Right 4/64 (6%) 2/2
Left 5/64 (8%) 3/2
Hydrocoele 13/35 (37%)
Prominent veins 16/71 (23%) 9/7
Cellulitis 14/71 (20%) 1/3
"Ski jump" toenails 10/71 (14%) 5/5
Papillomatosis 7/71 (10%) 5/2
Urethral abnormality 3/71 (4%) 3/0

Family demographics
Following ascertainment via an affected proband, 211 individuals from 10 families, including unaffected spouses, were examined because of a family history of congenital lymphoedema. Of these, 64 (31M/33F) were found to be clinically affected with limb swelling or characteristic skin changes. All those thought to be clinically affected were found to carry VEGFR-3 mutations. Seven (10%) clinically unaffected individuals (4M/3F), including three obligate gene carriers, were found to carry mutations in the absence of clinical signs. Following clinical review of these gene carriers, in light of their molecular analysis, initial impressions of their unaffected status have not changed. As only two out of 64 affected gene mutation carriers developed oedema later in life, it is unlikely, though still possible, that these seven individuals will develop oedema.

Clinically there was marked inter- and intrafamilial variation in the degree of oedema, ranging from only toes affected to bilateral swelling to the groin.

Age of onset
Of the 64 clinically affected individuals, 62 reported swelling from birth, with the two remaining individuals (1M/1F) reporting swelling first noted at ages 25 and 46, respectively. In two cases, where severe swelling of the dorsum of the foot was present at birth, oedema had reduced substantially by the age of 5. In all other cases the extent of swelling reportedly remained largely unchanged over time in contrast to lymphoedema-distichiasis, which tends to progress. Sclerosis of the skin with limited pitting seems to be a characteristic of Milroy disease and presumably limits swelling.

Distribution of swelling
Bilateral leg swelling was present in 55/64 (26M/29F) individuals. Of these, leg swelling was asymmetrical in 20 (12M/8F). An additional nine individuals were affected unilaterally (5M/4F). Expression ranged from no clinically evident swelling in seven individuals (10%) to severe, bilateral swelling to the groin in two cases. Gender did not influence the degree of swelling.

Urological abnormalities
Of the 35 males with VEGFR-3 mutations, 13 (37%) had developed a hydrocoele. In three of the 13 cases, bilateral hydrocoeles were reported, including a gene carrier with no lymphoedema when examined at the age of 42. Three male patients underwent surgery in childhood for urethral abnormalities; two were described as urethral stricture and the third as mild hypospadias. A fourth individual had an operation on the penis at birth but details were unclear and this may have been for severe oedema causing phimosis.

Veins
True varicose veins were present in only three individuals, with only two females having undergone surgical procedures for the condition. Sixteen individuals were however noted to have large calibre but non-tortuous long saphenous veins (fig 1). These veins were not painful and not associated with any skin signs of venous disease.

Other phenotypic abnormalities
Upslanting of the nail on the big toe ("ski-jump" toenails), apparently present from birth, was noted in 10 patients (fig 2). In eight individuals the nails on the big toe were abnormally thickened and yellow in colour. Papillomatosis was noted on the toes of seven individuals. In all cases the papillomas were present over the base of the second toe (fig 3). All of these features can be secondary to lymphoedema of any cause.

There were no consistent dysmorphic features in the affected individuals.

Infection
Cellulitis was reported as a recurring problem in 14 cases (11M/3F) with males significantly more likely to be affected (Fisher’s exact test, p = 0.015). Several patients were taking long term prophylactic antibiotics. Generalised problems with immunity were not evident from medical histories.

Lymphangiography/lymphoscintigraphy
Ten patients had undergone either lymphangiography or lymphoscintigraphy. In all four cases where lymphangiography was successful, lymphatic hypoplasia was noted. Two attempts at lymphangiography failed due to lack of lymphatics in the foot. The lymphoscintigram results in all six cases showed no, or little, uptake by peripheral lymphatics in the foot and consequently no, or little, uptake in the ilio-inguinal nodes (fig 4).

Treatment
On presentation to the clinic only 16 patients were having active treatment for lymphoedema. Treatments were limited to massage and compression with hosiery or pneumatic therapy. Two female patients had undergone surgery; one had unilateral reduction surgery in childhood, while the other had removal of papillomas from the dorsum of the toes in her twenties.

Molecular resultsAll 71 patients had mutations within one of the two kinase domains of VEGFR-3. Details of all mutations have previously been published.16

Discussion

Phenotypic abnormalities are described in 71 individuals with mutations in VEGFR-3 (Milroy disease). Seven were found to carry disease causing mutations but were clinically unaffected. Of the 64 clinically affected individuals with VEGFR-3 mutations, below knee swelling, usually bilateral, was the most consistent finding. While onset at birth has been a requirement for the clinical diagnosis of Milroy disease, two individuals with mutations appeared to develop swelling much later in life, although it is possible subtle early changes may have been missed. Other investigators have also found that the majority of VEGFR-3 mutation carriers develop congenital swelling but rare cases appear later in life.18 In males, hydrocoele is the next commonest manifestation after swelling. Cellulitis is significantly more common in males, as was reported in association with lymphoedema-distichiasis syndrome.13

Milroy disease has frequently been confused with other forms of congenital lymphoedema. This study excluded families without mutations in order to refine the phenotype of those with clinical Milroy disease and a VEGFR-3 mutation. Clearly, not all individuals with Milroy disease will have identifiable mutations in VEGFR-3. Milroy disease should be considered if the lymphoedema is congenital and confined to the lower limbs. The swelling is frequently "woody" in nature and associated with secondary changes which include deep creases over the toes, small dysplastic ("ski jump") toenails, and papillomas. The prominent wide calibre leg and foot veins are often a good clue to the underlying diagnosis as they are not seen with other causes of congenital lymphoedema.

Unlike other syndromes associated with lymphoedema, there are few associated abnormalities. Apart from hydrocoeles and some urethral abnormalities, there were no major structural abnormalities or consistent dysmorphic features.

VEGFR-3 is one of the most important genes responsible for lymphangiogenesis. Transgenic mice that are homozygous for VEGFR-3 mutations die before birth as a consequence of severe cardiovascular abnormalities.19 Chy mice (VEGFR-3+/–) and mice in which the VEGFR-3 receptor is blocked, develop hind limb oedema similar to Milroy disease.20 In these mice fluorescence microlymphangiography failed to demonstrate functioning skin lymphatics (as was described in three human cases of Milroy disease21). Chy mice develop chylous ascites and some die soon after birth. In those that survive, chylous ascites resolves spontaneously never to reappear. No cases of chylous ascites have been described in those patients with VEGFR-3 mutations. To what extent transient ascites occurs in utero but then resolves is uncertain, but there have been no reports of this occurring.

Despite the germline mutation, lymphoedema appears to develop only in the lower limbs of humans or the hindlimbs of transgenic mice, but the reason for this is not clear. The onset of oedema at birth, before walking begins, suggests that orthostatic factors are not responsible for the limitation of oedema to the lower limbs. A failure to detect peripheral lymphatics with vital dyes prior to radiocontrast lymphography22 or a failure of uptake of radiotracers by initial lymphatics during lymphoscintigraphy, as seen in six of our patients, would be in keeping with a failure in development of the most peripheral lymphatic vessels in the lower limbs.
Although there was a suggestion of hand swelling in one patient examined at the age of 1 year, our experience has shown that it is often difficult to differentiate between oedematous and normal skin in young children.7 Follow up of this patient has not been possible.

Because VEGFR-3 is involved in cardiovascular development before the receptor becomes restricted to the lymphatic endothelium, one could have expected some cardiovascular abnormalities, but none were observed. The finding of large calibre long saphenous veins needs further investigation. Venous disease does not obviously develop in Milroy disease, unlike in lymphoedema-distichiasis syndrome.13

The finding of urethral stricture in two patients and hypospadias in a third is of interest. The majority of cases of urethral stricture in the general population are acquired, with the congenital form being extremely rare. Hypospadias occurs in less than 1% of male births. Our findings may be coincidental, but with an incidence of 8% in males in our series it is likely to be a true association, although there is no clear common embryological origin between the urethra and lymph system.23

The apparent non-penetrance of oedema in 10% of individuals with a VEGFR-3 mutation is important from a counselling point of view, both in terms of reproductive risk estimation and possible cosmetic effects of the condition.

For clinical purposes we propose that the term Milroy disease should be reserved only for those cases of primary lymphoedema which conform to the criteria proposed by Milroy: familial (autosomal dominant inheritance), congenital onset, non-progressive, lower limb involvement. However, theoretically, new dominant mutations may occur, or the parent may be non-penetrant. VEGFR-3 analysis in these situations would be helpful.

Theoretically, gene therapy would be an option for treatment particularly as successful reversal of the phenotype has been achieved in transgenic mice.24,25

Acknowledgements

This research was conducted within the network of the London IDEAS Genetic Knowledge Park. The research also utilised the services of the Biomics Unit of St George’s Hospital Medical School.

Footnotes

RB and GB were supported by the British Heart Foundation. AHC was supported by the Bluff Field Charitable Trust. MS was supported by National Heart, Lung and Blood Institute, Grant #: R01-HL66150.
Conflict of interest: none declared.

This study had the approval of the Wandsworth Local Research Ethics Committee and the University of Connecticut Health Center Institutional Review Board. Written consent was obtained from all participants or, in the case of a child, from their parent.

British Medical Journal