Clinical Guidance

No genotype-phenotype correlation for Milroy disease has been reported. Most pathogenic variants are missense variants that occur in the tyrosine kinase domain of FLT4 .

Source: GeneReviews — "Milroy Disease"

Penetrance

Approximately 85%-90% of individuals who have a pathogenic variant in FLT4 develop lower-limb lymphedema by age three years; conversely, 10%-15% of individuals with an FLT4 pathogenic variant are clinically unaffected.

Source: GeneReviews — "Milroy Disease"

Diagnostic Criteria

Suggestive Findings

Milroy disease should be suspected in individuals with the following clinical features, radiographic findings, and family history.

Clinical features

• Lower-limb swelling that is:

• Usually (not always) bilateral

• Present at birth or develops soon after

Note: In neonates the swelling predominantly affects the dorsum of the feet; with age, the swelling may improve or progress to affect the below-knee region (rarely extending above the knees).

• Large-caliber veins below the knees

• Upslanting and small, dysplastic toenails

• Deep interphalangeal creases of the feet

• Hydroceles in males

• No internal clinically significant lymphatic issues (e.g., intestinal lymphangiectasia, pleural or pericardial effusions)

Source: GeneReviews — "Milroy Disease"

Differential Diagnosis

A list of differential diagnoses can be found in .

Table 2.

Genes of Interest in the Differential Diagnosis of Milroy Disease

Gene(s) | DiffDx Disorder | MOI | Lymphedema Phenotype of DiffDx Disorder | Other Clinical Features

ADAMTS3

| Hennekam lymphangiectasia-lymphedema syndrome 3 (OMIM 618154) | AR | Congenital generalized edema | Assoc features incl facial dysmorphism protein-losing enteropathy of variable severity

BRAF

KRAS

LZTR1

MAP2K1

NRAS

PTPN11

RAF1

RIT1

Source: GeneReviews — "Milroy Disease"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Milroy disease, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Milroy Disease

Source: GeneReviews — "Milroy Disease"

Clinical Guidance

The following should be avoided:

• Wounds to the swollen limbs, because of a reduced resistance to infection

• Long periods of immobility with the legs in a dependent position (e.g., on a long airplane flight)

• Medications that can cause increased leg swelling in some individuals (particularly calcium channel-blocking drugs)

Source: GeneReviews — "Milroy Disease"

Therapies Under Investigation

Attempts at overexpressing VEGF-C, the ligand for FLT4, have been successful in producing functional lymphatics in mice . This treatment approach (in combination with microsurgical lymph node transfer surgery) is now being studied in humans in a clinical trial for breast cancer treatment-related secondary lymphedema . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Milroy Disease"

Surveillance Guidelines

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

Source: GeneReviews — "Milroy Disease"