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

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.

Dysfunction of dermal initial lymphatics of the arm and upper body quadrant causes congenital arm lymphedema.

OBJECTIVE: The objective of this study was to explore the pathologic process underlying primary lymphedema. METHODS: Twenty-seven patients with unilateral congenital arm lymphedema who visited our clinic from January 1, 2014, to May 30, 2019, were enrolled. The patients' clinical signs and the findings of indocyanine green (ICG) lymphography, skin tissue immunohistochemical staining, and whole exome sequencing of tissue and blood were evaluated. RESULTS: Among the 27 patients, 11 were diagnosed with stage II and 16 were diagnosed with stage III lymphedema. No lymphatic vessels were visualized in the affected arm in 25 of 27 (93%) patients who underwent ICG lymphography; likewise, no lymphatics were found in the territories of axillary lymph node drainage in the trunk, irrespective of any anomalies of the axillary lymph nodes. In only two (7%) patients, an unclear lymphatic trunk gradually appeared in the dorsum of the affected hand. The number of initial lymphatics was increased in the skin specimens of all nine patients in whom lymphatics were not demonstrated by ICG lymphography. Among 14 tested patients, we found compound heterozygote variants in the PIEZO1 gene in only one (7%) patient. Two missense variants, c.4072C>T; p.Arg1358Cys and c.5033C>T; p. Ala1678Val, were identified and found to have been inherited from the father and mother, respectively. No other pathogenic or likely pathogenic variants of currently known lymphedema-related genes were identified in the remaining 13 patients. No genetic difference was found between the lymphedematous and nonedematous healthy skin tissue of the same person. CONCLUSIONS: Segmental or regional dysfunction of the dermal initial lymphatics causes congenital arm lymphedema and may have implications for clinical treatment.