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Pulmonology > Idiopathic Lung Disorders
Milroy Disease
Article Last Updated: Jun 21, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Raphael J Kiel, MD, Associate Professor of Medicine, Wayne State University School of Medicine; Associate Program Director, Head of Infectious Disease Section, Department of Internal Medicine, Oakwood Hospital
Raphael J Kiel is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Geriatrics Society, American Medical Association, and American Medical Informatics Association
Editors: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Gregg T Anders, DO, Medical Director, Great Plains Regional Medical Command, Brook Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Author and Editor Disclosure
Synonyms and related keywords:
Milroy disease, congenital lymphedema, lymphedema congenita, noninfectious hereditary elephantiasis, autosomal dominant lymphedema, lymphatic obstruction, fibrosis, cellulitis, Meige disease, lymphedema tarda, lymphedema praecox
Background
Lymphedema is characterized by swelling of the soft tissue secondary to obstruction of lymphatic drainage. Lymphatic obstruction causes an increase in the protein content of the extravascular tissue with subsequent retention of water. The increase in the extravascular protein stimulates proliferation of fibroblasts, organization of the fluid, and development of a "woody feeling" nonpitting swelling of the affected extremity. Fibrosis also obstructs the lymphatic channels and leads to increased protein concentration in the tissues, continuing this cycle. Lymphedema opens channels in the integument and allows bacteria to enter the subcuticular space, which overwhelms host defenses and leads to cellulitis of the extremity.
Lymphedema is classified into primary and secondary forms. Secondary lymphedema occurs as a result of obstruction of lymphatic flow by known mechanisms, ie, filariasis, silica, obstruction by a proximal mass, postsurgical mechanisms (eg, mastectomy), and fibrosis secondary to chronic infections.
Primary lymphedema is divided into 3 groups based on age of onset. Congenital lymphedema that is present at birth and associated with an autosomal dominant familial history is called Milroy disease. Lymphedema praecox (Meige disease) occurs after birth but before 35 years; the age of onset is generally in adolescence. Lymphedema tarda occurs in individuals older than 35 years. Of patients with primary lymphedema, 10% have Milroy disease, 80% have lymphedema praecox, and 10% have lymphedema tarda (manifesting in persons older than 35 y).
Pathophysiology
Hypoplasia, dilation, and tortuosity of lymphatic structures characterize primary lymphedema. Failure of adequate clearance of lymphatic fluid leads to accumulation of protein in the extracellular fluid. Fibroblasts are stimulated, and the swelling becomes organized and nonpitting. Obstruction of normal lymph flow predisposes patients to recurrent infection with streptococci or staphylococci. These infections cause more lymphatic destruction and predispose patients to prolonged episodes of lymphedema and recurrent bacterial infection.
A tyrosine kinase receptor specific for lymphatic vessels has been reported to be abnormally phosphorylated in patients with Milroy disease. The gene for this disease, VEGFR3 (FLT4), has been mapped to the telomeric part of chromosome arm 5q in the region 5q34-q35. VEGFR3 is expressed in the adult lymphatic endothelial cells. Studies in transgenic mice with overexpression of VEGFR3 ligands demonstrate the formation of new hyperplastic lymphatics. Induction of this gene may provide a potential target for future interventions in this patient population.
Frequency
United States
The primary lymphedemas occur in 1 of 10,000 individuals. Milroy disease is inherited as an autosomal dominant condition associated with variable penetrance. It is not observed as commonly as lymphedema praecox (Meige disease), which constitutes 80% of cases of primary lymphedema. Actual incidence of Milroy disease is unknown because most patients have been reported in small case-based studies. Approximately 200 cases have been described in the literature.
Mortality/Morbidity
- Primary lymphedema usually does not progress. The condition stabilizes after several years of activity.
- Patients may have recurrent streptococcal cellulitis and lymphangitis, with subsequent hospitalizations for antibiotic therapy.
- A rare complication is the appearance of lymphangiosarcoma or angiosarcoma in patients with persistent lymphedema. Some patients may develop protein-losing enteropathy and visceral involvement. Chylous ascites and chylothorax rarely occur.
Race
Milroy disease has no known racial predilection.
Sex
Milroy disease affects both sexes; however, 70-80% of cases occur in females.
Age
By definition, Milroy disease occurs in infants and is present at birth. Lymphedema praecox occurs in individuals younger than 35 years, usually in adolescents.
History
- Edema occurs at birth and is firm to the touch, although pitting may occur with pressure. The temperature of the overlying skin is increased.
- The right lower extremity is preferentially involved. Generally, the edema involves the dorsum of the foot and does not extend beyond the level of the knee.
- Usually, several other family members have a history of congenital lymphedema.
Physical
- Brawny edema of a lower extremity is present at birth but usually does not extend above the knee. As the edema becomes chronic, a woody feel to the tissue may develop, signaling progressive tissue fibrosis.
- The overlying skin often exhibits a rosy hue.
- Patients may have involvement of the external genitalia as a result of associated lymphatic abnormalities, and some may have a cystic hygroma of the neck.
Causes
- The cause of Milroy disease is the failure of lymphatic vessels to develop in utero.
- On a cellular level, Milroy disease has been related to defective VEGFR3 signaling mapped to a part of chromosome arm 5q. This region codes for a tyrosine kinase receptor specific for the function of the lymphatic vessels.
Arteriovenous Malformations
Cellulitis
Lymphedema
Meigs Syndrome
Other Problems to be Considered
Neurofibromatosis
Sclerema neonatorum
Lab Studies
Imaging Studies
- Ultrasound of the leg can exclude vascular abnormalities such as arteriovenous fistula.
- Plain radiographs can exclude abnormalities of the bone.
- After a subcutaneous injection of dye, lymphangiography of patients with Milroy disease shows lymphatic vessels that cannot be cannulated.
- Lymphoscintigraphy using the subcutaneous injection of technetium-labeled colloid demonstrates an absence of lymphatic vessels.
- MRI can also be used; however, it is more useful to show lymph trunk anatomy and causes of obstructive secondary lymphedema.
Procedures
- Biopsy of the skin is performed using standard techniques. A 25-gauge needle is used to infiltrate the skin with local anesthesia. The skin is stretched perpendicular to the desired line of the scar. A punch biopsy tool is rotated into the skin to obtain a small circle of tissue, which is sent to pathology for histologic staining. Bleeding is controlled by the application of pressure to the area or by the use of a single suture. Topical antibiotics applied twice daily speed wound healing.
Histologic Findings
Early in the disease, lymphatic vessels are conspicuously absent upon biopsy. Late in the disease, histology shows lymphangiectasia and fibrosis involving the subcutaneous skin.
Medical Care
Treatment of patients with hereditary lymphedema is primarily directed against the prevention of infection and the control of local complications of limb swelling. Studies in mice, however, suggest that induced overexpression of VEGFR3 ligands stimulate the growth of functional lymphatic vessels. An increase in lymphatics would benefit patients with primary and secondary lymphedema.
- Exercise and elevation of the extremity promote movement of fluid away from the lower extremity.
- Elastic stockings and bandages are applied in a gradient fashion, with the highest compression distally and no constriction points.
- Gentle massage or pneumatic compression can be used.
- Proper skin hygiene and use of skin moisturizers prevents drying and fissuring of skin and subsequent bacterial skin infections.
- Use an antistreptococcal antibiotic to treat recurrent cellulitis. Prophylactic antibiotic therapy, such as benzathine penicillin in low doses, may be used to prevent intermittent cellulitis. Antibiotics directed at prophylaxis should have good activity against Streptococcus pyogenes.
- No medication treats or prevents Milroy disease. Complications of this disease, including cellulitis, bacteremia, and chylothorax, are treated as required. Benzopyrones, such as coumarin or diosmin, may stimulate proteolysis of tissue proteins.
Surgical Care
- Several surgical methods have been attempted to benefit patients with Milroy disease, but none has achieved lasting success.
- Excision of the fibrotic subcutaneous tissues with coverage by split-thickness skin grafts has been described.
- Pedicular transfer of skin with healthy lymphatics to the affected limb and anastomosis to existing lymphatic channels has been tried without much success.
Consultations
- Consultation with an infectious disease specialist is indicated for the treatment of recurrent cellulitis.
- In the future, consultation with a geneticist will provide insights into familial inheritance patterns.
Activity
Encourage patients to exercise after a graded support is applied to the involved extremity.
No medication treats or prevents Milroy disease. Complications of this disease, including cellulitis, bacteremia, and chylothorax, are treated as required. Antistreptococcal antibiotics (eg, cefazolin, clindamycin) can be used to treat cellulitis. Monthly penicillin G benzathine injections may be required to prevent recurrent cellulitis.
Drug Category: Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.
| Drug Name | Cefazolin (Ancef) |
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| Description | First-generation semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth. Primarily active against skin flora, including Staphylococcus aureus. Typically used alone for skin and skin-structure coverage. IV and IM dosing regimens are similar. |
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| Adult Dose | 250 mg to 2 g IV/IM q6-12h, depending on severity of infection; not to exceed 12 g/d |
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| Pediatric Dose | 25-100 mg/kg/d IV/IM divided q6-8h, depending on severity of infection; not to exceed 6 g/d |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Probenecid prolongs effect; coadministration with aminoglycosides may increase renal toxicity; may yield false-positive urine-dip test results for glucose |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Adjust dose in renal impairment; superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy |
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| Drug Name | Clindamycin (Cleocin) |
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| Description | Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (but not enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. |
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| Adult Dose | 150-450 mg/dose PO q6-8h; not to exceed 1.8 g/d; 600-1200 mg/d IV/IM divided q6-8h, depending on degree of infection |
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| Pediatric Dose | 8-20 mg/kg/d PO as hydrochloride and 8-25 mg/kg/d PO as palmitate divided tid/qid; 20-40 mg/kg/d IV/IM divided tid/qid |
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| Contraindications | Documented hypersensitivity; regional enteritis, ulcerative colitis, hepatic impairment, antibiotic-associated colitis |
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| Interactions | Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Adjust dose in patients with severe hepatic dysfunction; no adjustment necessary in patients with renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile |
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| Drug Name | Penicillin G benzathine (Bicillin) |
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| Description | Interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. Used to treat syphilis and for prophylaxis of recurrent streptococcal infections. |
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| Adult Dose | 1.2 million U IM qmo |
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| Pediatric Dose | 25,000-50,000 U/kg IM qmo; not to exceed 1.2 million U/dose |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Probenecid can increase effectiveness by decreasing clearance; coadministration with tetracyclines can decrease effectiveness |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Caution in patients with impaired renal function |
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Drug Category: Anticoagulants
May stimulate proteolysis of tissue proteins.
| Drug Name | Warfarin (Coumadin) |
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| Description | Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor dose to maintain INR of 2-3. |
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| Adult Dose | 5-15 mg/d PO for 2-5 d; adjust dose according to desired INR |
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| Pediatric Dose | 0.05-0.34 mg/kg/d PO; adjust dose according to desired INR |
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| Contraindications | Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers |
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| Interactions | Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate; medications that may increase anticoagulant effects include oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Do not switch brands after achieving therapeutic response; caution in patients with active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis |
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Further Inpatient Care
Further Outpatient Care
- See patients monthly to teach the parents proper noninvasive methods of controlling swelling of the extremity.
- Instruct parents to bring the child in for evaluation if fever associated with redness and further swelling of the extremity occurs.
Transfer
- Generally, treatment of the patient can occur in a general hospital setting. If difficulty with proper intravenous access occurs, consider transfer to a pediatric hospital.
Deterrence/Prevention
- Milroy disease is a genetically transferred illness. Watch for the development of complications of the disease (eg, cellulitis, lymphangiosarcoma).
- Prenatal screening for the presence of an abnormal gene sequence may provide parents with additional information on the possibility of their child developing Milroy disease.
Complications
- Recurrent cellulitis
- Bacteremia
- Lymphangiosarcoma
- Sarcoma
- Protein-losing enteropathy
- Chylothorax
- Chylous ascites
Prognosis
- Long-term prognosis is excellent.
Patient Education
- Milroy disease is a genetically transmitted swelling of an extremity that is present at birth and is usually not progressive. Patients develop lymphedema and can experience recurrent cellulitis, but the disease does not decrease their lifespans.
Medical/Legal Pitfalls
- Physicians should be aware of Milroy disease and recognize the condition's associated familial pattern. Extensive searching for a secondary cause of this condition could result in undue morbidity for the patient.
- Physicians should be aware of the possibility of recurrent cellulitis associated with this disease, and they should establish a treatment plan with the parents that protects the child from potential complications.
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Milroy Disease excerpt Article Last Updated: Jun 21, 2006
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