Abstract

Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention.