Defective development of the peripheral lymphatic system: Lymphatic malformations

Abstract Lymphatic malformations (LMs) are one grouping of numerous forms of congenital vascular malformations (CVMs), affecting only the lymphatic system as the outcome of defective development during various stages of lymphangiogenesis. LM is caused by a developmental arrest in the “earlier” stages of lymphangiogenesis and is classified to the “extratruncular” lesion (also known as “lymphangioma”), since it maintains “evolutional potential” and a unique embryonic characteristic that originates from the mesenchymal cells. LM caused by the lesion/defective development during the “later” stage of lymphangiogenesis is defined as “truncular” lesion (also known as “primary lymphedema”), with no such evolutional potential to grow (cf. extratruncular). LM lesions can present as a solitary independent lesion or coexist with other CVMs, often as a hemolymphatic malformation (HLM). This combined form of the CVM is commonly one of the vascular malformation components of “syndromic” entities (e.g., Klippel-Trenaunay syndrome). All primary lymphedema clinically manifesting as a truncular LM, with a macroscopic structural abnormality, is the outcome of heritable abnormal structural development. Such inherited conditions are caused by the mutation of any of the genes involved in the lymphatic system development. The identification of the genetic causes of primary lymphedema provides a molecular diagnostic test for some subtypes. Patients and families benefit hugely from a molecular diagnosis, because it allows the clinician to confidently predict the clinical prognosis and offer screening for family members. This chapter will discuss LMs and CVMs in detail, proving general and embryonic aspects of the malformations, along with clinical and management options for patients.