PRIMARY LYMPHOEDEMA Aetiology It has been proposed that all cases of primary lymphoedema are due to an inherited abnormality of the lymphatic system, sometimes termed 'congenital lymphatic dysplasia'. Genetic susceptibility Primary lymphoedema can be familial or sporadic. In familial cases the genetic mutations can be inherited in an autosomal dominant, recessive or x-linked pattern. In the last few years the application of Next Generation Sequencing, which allows identification of genetic mutations, even in sporadic cases and smaller families, has increased our understanding of the genetic basis of lymphoedema. So far, mutations in more than 20 genes have been linked to the development of primary lymphoedema. In individuals with familial mutations the penetrance of lymphoedema can often be incomplete leading to a large variability in clinical presentation. Involvement of other systems (cardiovascular, respiratory, nervous, digestive) is common and can indicate a specific mutation. Presence of isolated lower limb lymphedema at bih, classically described as Milroy's disease, suggests mutation in FMS-like tyrosine kinase 4 (FLT4)/ vascular endothelial growth factor receptor-3 (VEGFR-3) or VEGF-C. In these patients, reduced initial uptake and presence of touous lymphatic tracts with evidence of rerouting in lymphangiography suggests mutation in the VEGF-C gene. lymphoedema can also be present as a minor sign in some well-recognised syndromes. Primary lymphoedema is present in less than 10% of cases of tuberous sclerosis (TSC1 and 2 gene mutations). Lymphoedema has been repoed in patients with Noonan syndrome in the presence of PTPN11, SOS1 or KRAS mutations, and in patients with Turner syndrome (monosomy X) and capillary malformation-aeriovenous malformation syndrome (RAS p21 protein activator 1 (RASA1) mutation). Ref : Bailey and love 27th edition Pgno : 1001