Radiologic phenotyping of two PIK3CA-related overgrowth spectrum cases: distinguishing FAO and CLOVES syndrome

Abstract Background PIK3CA-related overgrowth spectrum (PROS) comprises a heterogeneous group of mosaic disorders characterized by segmental overgrowth and vascular anomalies. Although genetic confirmation is considered the diagnostic gold standard, it is often limited by mosaicism and availability, necessitating integration of clinical examination, imaging findings, and molecular testing when available for accurate diagnosis and phenotypic classification. Case presentation We present two pediatric cases representing distinct phenotypes within the PROS continuum. The first case demonstrated congenital unilateral enlargement of the left upper extremity, with MRI revealing predominant subcutaneous adipose hypertrophy without evidence of vascular malformation, consistent with fibroadipose overgrowth (FAO). The second case was identified prenatally on fetal MRI as a large, multiloculated cystic lesion involving the retroperitoneum, abdominal wall, pelvis, and left lower extremity. Postnatal imaging confirmed a complex, trans-spatial slow-flow veno-lymphatic malformation with associated adipose overgrowth, most consistent with the CLOVES phenotype within the PIK3CA-related overgrowth spectrum. Longitudinal imaging guided both diagnosis and management. Discussion Imaging plays a central role in differentiating PROS entities based on dominant tissue characteristics and vascular dynamics. FAO is defined by adipose-predominant overgrowth without a vascular nidus, whereas CLOVES syndrome demonstrates extensive slow-flow vascular malformations with multi-compartment involvement. Notably, both cases exhibited left-sided predominance, consistent with reported PROS patterns. Conclusion Radiologic phenotyping enables accurate classification within the PROS spectrum and guides management, even in the absence of genetic confirmation.