FLT4 – Lymphatic Malformation 1 (Milroy Disease)

FLT4 encodes vascular endothelial growth factor receptor 3 (VEGFR3), a tyrosine kinase critical for lymphatic vessel development. Heterozygous missense mutations in FLT4 underlie autosomal dominant congenital lymphedema type I, also known as Milroy disease or lymphatic malformation 1 (Gene Symbol; Disease Name). The disease is characterized by lower limb lymphedema at birth, with onset from the neonatal period in most cases and variable expressivity including unilateral or hemi-lymphedema.

Genetic studies have identified over 100 pathogenic FLT4 variants in more than 200 affected individuals across at least 95 unrelated families, predominantly clustering within the intracellular tyrosine kinase domains (PMID:23074044). Missense changes such as c.2569G>A (p.Gly857Arg) and c.3104A>G (p.His1035Arg) account for a large proportion of cases and cosegregate with disease in multiple multigenerational pedigrees (PMID:15904433; PMID:10856194). More recently, rare hypomorphic variants including c.2563G>A (p.Ala855Thr) have been reported in recessive presentations, expanding the allelic and inheritance spectrum (PMID:19289394).

Segregation analysis demonstrates full or near–full penetrance in autosomal dominant kindreds, with more than 71 affected relatives confirmed to carry kinase domain variants (PMID:15689446). No unaffected carriers have been documented in well‐phenotyped families. The variant spectrum includes 26 missense mutations, two splice or non‐frameshift changes, and over 50 unique recurring alleles, but no large copy‐number variants have been described.

Functional assays across multiple studies reveal that Milroy‐associated FLT4 missense mutations inhibit receptor autophosphorylation and downstream ERK1/2 signaling, consistent with a dominant‐negative or haploinsufficiency mechanism (PMID:10856194; PMID:23074044). Knock‐in mouse and zebrafish models recapitulate lymphatic defects, and in vitro expression of kinase‐dead receptor variants abolishes ligand‐induced internalization and signaling.

Clinically, Milroy disease presents with congenital symmetric or asymmetric lower limb edema, increased risk of cellulitis, papillomatosis, large‐caliber leg veins, and hydrocele in males (PMID:15689446). Rarely, severe lymphatic dysplasia leads to nonimmune hydrops fetalis. MR lymphangiography and indocyanine green imaging demonstrate segmental lymphatic aplasia and tortuosity in affected individuals.

In summary, FLT4 and lymphatic malformation 1 exhibit a definitive gene–disease relationship based on extensive genetic and functional evidence. Molecular testing of FLT4 should be pursued in all patients with congenital lymphedema to inform diagnosis, prognosis, and potential therapeutic targeting of VEGFR3 signaling. Key Take-Home: FLT4 missense mutations cause Milroy disease via impaired VEGFR3 kinase activity, guiding genetic diagnosis and exploration of receptor‐targeted interventions.

References

• American Journal of Human Genetics • 2000 • Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase PMID:10856194
• Human Mutation • 2013 • FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update PMID:23074044

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