Milroy Disease 

  • Author: Raphael J Kiel, MD; Chief Editor: Zab Mosenifar, MD   more...
 
Updated: Oct 14, 2010
 

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.[1] Congenital lymphedema that is present at birth and associated with an autosomal dominant familial history is called Milroy disease.[2] Lymphedema praecox (Meige disease) occurs after birth but before 35 years; the age of onset is generally in adolescence.[3] 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).

A related article posted on Medscape is " Diagnosis and Management of Lymphatic Vascular Disease."

An image depicting the lymphatic system can be seen below.

Lymphatic system, anterior view. Lymphatic system, anterior view.
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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.[4]

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, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4),[5, 6] has been mapped to the telomeric part of chromosome arm 5q in the region 5q34-q35.[7]VEGFR3 is expressed in the adult lymphatic endothelial cells. The literature suggests that failure of lymph absorption is not due to the absence of lymphatic drainage routes but due to dysfunction of the lymphatics that are present.[8] 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.

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Epidemiology

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.[9] 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.

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Contributor Information and Disclosures
Author

Raphael J Kiel, MD  Associate Professor of Medicine, Wayne State University School of Medicine; Associate Professor of Medicine, Oakland University William Beaumont School of Medicine; Consulting Staff, Infectious Diseases Division, William Beaumont Hospital; Consulting Staff, Infectious Diseases Division Providence Hospital

Raphael J Kiel, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Geriatrics Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Gregg T Anders, DO  Medical Director, Great Plains Regional Medical Command , Brooke Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio

Gregg T Anders, DO is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Timothy D Rice, MD  Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine

Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

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

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

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Lymphatic system, anterior view.
 
 
 
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