PIK3CA-related overgrowth spectrum: From genetic mechanisms to targeted treatment with alpelisib

Abstract

PIK3CA-related overgrowth spectrum (PROS) encompasses a range of rare disorders caused by somatic gain-of-function mutations in the PIK3CA gene, leading to extensive tissue overgrowth and complex vascular malformations. These conditions exhibit wide clinical variability and often present with asymmetric segmental overgrowth involving multiple tissue types, including fat, muscle, bone, and nervous tissues. Conventional treatments, such as debulking surgery or mammalian target of rapamycin inhibitors such as sirolimus, offer only limited, temporary benefits and have potential side effects. Recently, alpelisib, a selective phosphatidylinositol 3-kinase α inhibitor, has emerged as a promising targeted therapy for PROS, demonstrating significant clinical improvements in reducing lesion size and symptom severity in patients with severe cases. The Food and Drug Administration’s accelerated approval of alpelisib for PROS by 2022 underscores its therapeutic potential; however, its long-term safety profile and applications in infants remain under investigation. This review examines the heterogeneous phenotypes, genetic and molecular basis of PROS, current evidence supporting alpelisib, and general prognosis of patients with PROS. Advances in genetic testing combined with a multidisciplinary approach to care offer promising avenues for enhancing both the management and quality of life of individuals affected by this complex spectrum of disorders.