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.”
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. 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.
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.
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.8 Some patients may develop protein-losing enteropathy and visceral involvement. Chylous ascites and chylothorax rarely occur.
Milroy disease has no known racial predilection.
Milroy disease affects both sexes; however, 70-80% of cases occur in females.
By definition, Milroy disease occurs in infants and is present at birth. Lymphedema praecox occurs in individuals younger than 35 years, usually in adolescents.
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.
Patients may also present with recurrent cellulitis, papillomatosis, large caliber leg veins, and upsloping “ski-jump” toenails.9
Hydrocele was the second most common presentation after edema in males.
Usually, several other family members have a history of congenital lymphedema.
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.
Hemorrhagic verruciform xanthoma is described on the dorsum of the toes.10
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.
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.