FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease

Abstract

This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.

Recurrent Left-Sided Pleural Effusions in a Patient With Chronic Lymphedema

“…Milroy's disease (hereditary lymphedema, type 1) is a rare inherited condition resulting in impaired lymphatic drainage due to a FLT4/VEGFR3 gene mutation [1][2][3]. The disease presents most commonly with bilateral lymphedema of the lower legs but can affect all extremities [1][2][3].…”

“…Milroy's disease is a rare genetic condition with a worldwide incidence of about 1/6000. It has an autosomal dominant inheritance [1][2][3] with a higher incidence in females [2]. It is a primary, hereditary source of lymphedema largely caused by genetic mutations in FLT4/VEGFR3, which are involved in lymphangiogenesis [1][2][3].…”

“…It has an autosomal dominant inheritance [1][2][3] with a higher incidence in females [2]. It is a primary, hereditary source of lymphedema largely caused by genetic mutations in FLT4/VEGFR3, which are involved in lymphangiogenesis [1][2][3]. FLT4/VEGFR3 abnormalities cause lymphatic aplasia or lymphatic collector dysfunction slowing the flow of lymph through defective nodes [1][2].…”

“…It is a primary, hereditary source of lymphedema largely caused by genetic mutations in FLT4/VEGFR3, which are involved in lymphangiogenesis [1][2][3]. FLT4/VEGFR3 abnormalities cause lymphatic aplasia or lymphatic collector dysfunction slowing the flow of lymph through defective nodes [1][2]. Symptoms of Milroy's disease occur early, with some cases reporting early bilateral dorsal edema symptoms at birth [3].…”

“…Symptoms of Milroy's disease occur early, with some cases reporting early bilateral dorsal edema symptoms at birth [3]. Milroy's disease often presents with bilateral swelling in differing distributions, but commonly affects the lower limbs and can affect all extremities [1][2][3]. Some complications of chronic lymphedema include infections/cellulitis [4], pleural effusions, septic arthritis, and intestinal lymphangiectasia [3].…”