Somatic PIK3CA Activating Mutation in a Plexiform Lesion of a Patient With HHT and PAH

Background: Hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH) are rare vascular diseases whose pathobiology is poorly understood. HHT is characterized by arteriovenous malformations, whereas PAH by an occlusive pulmonary vasculopathy that includes plexiform lesions. Case Summary: A female patient with PAH and HHT developed right heart failure with severe hypoxemia despite years of medical treatment for PAH, necessitating a heart-lung transplantation. Discussion: Histological and molecular analysis of the lung explant revealed that, in addition to the inherited HHT-causing variant in the endoglin gene, a plexiform lesion harbored an oncogenic, somatic phosphoinositide-3-kinase, PIK3CA activating mutation, which in this case may have driven endothelial cell proliferation. Take-Home Messages: This novel discovery sheds light on the molecular basis of plexiform lesion development in this rare case of combined PAH and HHT, highlighting a potential role of somatic mutations in driving endothelial cell proliferation in plexiform lesions.

Duke Scholars

Author Douglas Alan Marchuk Molecular Genetics and Microbiology