An Updated Classification of Primary Lymphedema Based on Age of Onset, Lymphatic Anomalies, and Genetics

Primary lymphedema (PLE) is a chronic disease caused by lymphatic dysplasia and progresses to irreversible tissue edema and hypertrophy. Understanding of PLE has been hitherto limited. The aim of this study is to devise an updated classification system for PLE of 1013 patients with PLE of lower limb were enrolled. Sex, age of onset, location, family history and morbidity were documented. The lymphatic imaging findings of magnetic reso-nance lymphography (MRL), indocyanine green lymphography (ICGL) and lymphoscin-tigraphy (LSG), skin tissue immunohisto-chemical staining, whole exome sequencing and the correlation of genotype-phenotype were evaluated. Patients were divided into a congenital onset category and a late onset category. The late onset category was further divided according to developmental age. The ratio of congenital-onset to late-onset PLE was 1:4 and that the highest incidence was in adolescence. The sex ratio was 1.04:1 and 1.5:1 in congenital-onset and late-onset groups, respectively. Three major lymphatic anomalies were identified, in which segmental lymphatic dysfunction, characterized by delayed or partial demonstration of lymph vessels, is the most common and associated with FLT4, GJC2, CELSR1, and PTPN14 mutations. The next most common type is lymphatic hyperplasia, which is associated with FOXC2 and GATA2 variants, followed by initial lymphatic aplasia or dysfunction, which is more common in pa-tients with congenital PLE and associated with FLT4 mutation. A functional and structural combined classification of lymphatic anomalies is proposed, which includes segmental lymphatic dysfunction, lymphatic hyperplasia and initial lymphatic aplasia or dysfunction.