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

Diagnosis/testing: The diagnosis of Milroy disease is established in a proband with congenital or infantile-onset lower-limb lymphedema accompanied by lack of uptake of radioactive colloid in the ilioinguinal lymph nodes on lymphoscintigraphy and/or by identification of a heterozygous pathogenic variant in FLT4 by molecular genetic testing.

Management: Treatment of manifestations: A lymphedema therapist may utilize fitted stockings and massage to improve the cosmetic appearance or decrease the size of the limb and reduce the risk of complications. Improvement in swelling is usually possible with use of properly fitted compression hosiery and/or bandaging and well-fitting, supportive shoes. Toe gloves may be of benefit and good skin care is essential. Standard treatment for cellulitis, hydroceles, and urethral abnormalities.

Prevention of secondary complications: Frequency of cellulitis can be reduced through good skin hygiene, prompt treatment of infections with antibiotics, and prophylactic antibiotics for recurrent episodes.

Surveillance: Routine follow up in a clinic specializing in the care of lymphedema is appropriate.

Agents/circumstances to avoid: Wounds to limbs; long periods of immobility with the legs in a dependent position; and medications that can cause increased leg swelling.

Evaluation of relatives at risk: Evaluation of apparently asymptomatic at-risk relatives of an affected individual is appropriate in order to identify those who would benefit from properly fitted compression hosiery and advice on how to reduce the risk of cellulitis of the legs and feet.

Genetic counseling: Milroy disease is inherited in an autosomal dominant manner. Most individuals diagnosed with Milroy disease have an affected parent. If a parent of the proband is affected and/or has an FLT4 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability and reduced penetrance are observed in Milroy disease; a heterozygous sib may be more or less severely affected than the proband. Once the FLT4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Ultrasonography during pregnancy may detect swelling of the dorsum of the feet, mild pleural effusions which often resolve, and (very rarely) more extensive edematous states (fetal hydrops) in an affected fetus.