BACKGROUND
Lymphedema is a common disabling condition and the most frequent lymphatic anomaly. It is characterized by chronic tissue swelling mostly located in the limbs. Lymphedema can be primary or secondary (acquired), the primary form resulting from inadequate development or function of the lymphatic system. Currently, germline mutations have been identified in 28 genes. However, these only explain approximately 40% of familial forms and 12% of sporadic forms, thus suggesting that other genes are involved. Mutations have recently been identified in the hepatocyte growth factor (HGF) gene in a group of primary lymphedema patients, and this gene has thus been proposed as a new player in the occurrence of primary lymphedema. Indeed, it has been identified as a strong promoter of lymphangiogenesis in various studies. Furthermore, an association between HGF and primary lymphedema has been reported in the literature, but only in two studies.
OBJECTIVES
In view of the paucity of available information, our study sought to clarify the contribution of HGF in the etiopathogenesis of lymphedema. Moreover, an accurate description of HGF mutation-associated phenotype was lacking, since the clinical features were only summarily mentioned in the two studies reporting an association between primary lymphedema and HGF. A major part of our study was thus dedicated to the innovative project of characterizing HGF phenotype. To a lesser extent, our study was also devoted to reviewing some of the well-known genes responsible for primary lymphedema. This review was illustrated by the analysis of seven cases of mutated primary lymphedema followed at the Cliniques Universitaires Saint Luc, Brussels.
MATERIALS & METHODS
A cohort of 542 patients were screened for mutations using a panel of 66 genes (including HGF), with 12 HGF variants identified in 11 patients. The clinical features of these 11 patients underwent in-depth analysis using a specific official lymphedema questionnaire along with the medical records, when available.
RESULTS & CONCLUSIONS
HGF mutations were found to be associated to isolated lateonset lower limb lymphedema, the severity of which varied depending on HGF residual activity. This study allowed an accurate delineation of the phenotypic spectrum of HGF mutations, thus justifying HGF mutations to be considered in the clinical differential diagnosis of the heterogeneous group of primary lymphedema. It also demonstrated the existence of a correlation between the phenotype and the genotype.