Vikkula, MiikkaGhalamkarpour, ArashArashGhalamkarpour2025-02-052025-02-052009https://dial-mem.test.bib.ucl.ac.be/handle/123456789/41140Introduction: Lymphoedema is defïned as régional accumulation of excessive interstitial protein-rich fluid. It results from low-output failure of the lymphatic System. There are two major categories of lymphoedema: primary (idiopathic) and secondary (acquired). Most primary lymphoedemas are sporadic; however, familial cases with varied inheritance patterns hâve been reported. Genetic studies on such families hâve revealed mutations in three lymphangiogenic genes. Mutations in VEGFR3 hâve been identified in a subset of patients with primary congénital lymphoedema or Nonne-Milroy disease. Individuals carrying a VEGFR3 mutation exhibit congénital oedema of the lower limbs, usually bilateral and below the knees, sometimes associated with cellulitis, prominent veins, papillomatosis, uptumed toenails, and hydrocele. Alterations in FOXC2 hâve been reported in association with lymphoedema-distichiasis (LD) syndrome, and the SOX18 mutations hâve been recognised in patients with hypotrichosis-lymphoedema-telangiectasia (HLT) syndrome. Nonne-Milroy disease and LD syndrome are autosomal dominant disorders, whereas, both autosomal dominant and récessive inheritance hâve been reported for HLT syndrome. Objectives: In order to study the phenotypic variations of lymphatic disorders with a genetic cause, we screened VEGFR3, F0XC2 and S0X18, as well as other genes implicated in lymphangiogenesis, such as PDPN and PROX1, in families/patients with manifestations of lymphatic failure. Results: Several VEGFR3 mutations were identified in classical Nonne-Milroy families. However, some of the patients had atypical présentations. One of the VEGFR3 mutations was identified in a large three génération family with congénital lymphoedema. This family had a wide intra-familial phenotypic variability including the index case who presented at 33 weeks’ gestation with polyhydramnios, massive bilateral hydrothorax, ascites, skin oedema and scalp oedema. This was the first report on association of hydrops fetalis with a VEGFR3 mutation. Further studies resulted in identification of a de novo VEGFR3 mutation in a patient with sporadic congénital lymphoedema. Moreover, three other families with a VEGFR3 mutation were identified; in each, one individual had an uncommon clinical présentation of Nonne-Milroy disease. These atypical présentations included prénatal pleural effusion, spontaneous résorption of lymphoedema and elephantiasis. Based on these findings, we hypothesised that de novo mutations in VEGFR3, or other lymphangiogenic genes, could explain sporadic occurrence of foetal oedema. Subséquent studies resulted in identification of two patients with sporadic prénatal generalised oedema and hydrops fetalis caused by a VEGFR3 mutation, and a patient with sporadic hydrops fetalis caused by a FOXC2 mutation. In these patients, the generalised oedema resorbed spontaneously, either in utero or after birth. In the two individuals with a VEGFR3 mutation, oedema remained limited to lower limbs. Finally, in one patient, the genetic cause of isolated primary congénital lymphoedema with récessive inheritance was identified. The patient had a homozygous VEGFR3 mutation. Assessment of mutated receptor function showed impaired ligand-induced internalisation and ERK1/2 activity. Moreover, receptor phosphorylation was reduced, although, less so than for a kinase-dead VEGFR3 mutation, which causes Nonne-Milroy disease. Conclusion: Identification of phenotypic variation associated with VEGFR3 mutations has important implications in genetic counselling, diagnosis and prédiction of prognosis. This is especially the case for atypical présentations, including sporadic patients with generalised subcutaneous oedema and hydrops fetalis, as well as congénital lymphoedema with récessive inheritance. Today, the treatment of lymphoedema is limited and mostly palliative. In long tenu, précisé diagnosis will direct studies that may lead to targeted therapy of these patients.text::thesis::master thesisthesis:49344