CLOVES syndrome

CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Scoliosis/Skeletal/Spinal anomalies) is a rare congenital overgrowth disorder caused by somatic (postzygotic) activating mutations in the PIK3CA gene. It belongs to the broader group of conditions known as the PIK3CA-related overgrowth spectrum (PROS). Because the mutation occurs after conception and affects only a subset of cells (mosaicism), the condition is not inherited from parents and presents with asymmetric, variable features depending on which tissues carry the mutation. CLOVES syndrome affects multiple body systems. Key features include truncal or limb lipomatous (fatty tissue) overgrowth that is typically present at birth, complex vascular malformations (including capillary, venous, lymphatic, and occasionally arteriovenous malformations), epidermal nevi (skin overgrowths), and skeletal anomalies such as scoliosis, limb length discrepancy, and broad feet or hands with wide sandal gaps between the toes. Patients may also develop renal and spinal abnormalities. A serious complication is the increased risk of thromboembolism and, rarely, Wilms tumor or other neoplasms. Management of CLOVES syndrome is multidisciplinary and largely symptomatic, involving orthopedic interventions for skeletal deformities, sclerotherapy or surgical debulking for vascular malformations, and dermatologic care for epidermal nevi. A significant advance in treatment has been the use of alpelisib (a selective PIK3CA inhibitor), which was approved by the FDA in 2022 for severe manifestations of PROS conditions including CLOVES syndrome. Alpelisib has shown the ability to reduce overgrowth and improve vascular malformations in affected patients. Lifelong monitoring for complications, including thrombosis and potential malignancies, is recommended.

Common questions about CLOVES syndrome