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Abstract PIK3CA -related overgrowth spectrum (PROS) comprises a heterogeneous group of disorders caused by postzygotic activating variants in PIK3CA , leading to mosaic activation of the PI3K pathway. PROS natural history is highly variable across patients and depends on the timing and distribution of the somatic mutation. To better characterize this natural history, we analyzed a cohort of patients with PROS. This multicenter study was conducted at Hôpital Femme Mère Enfant (Lyon, France) and Hôpital Necker-Enfants Malades (Paris, France). We included pediatric and adult patients with PROS who had a documented PIK3CA variant and at least two MRI examinations performed at least 2 months apart. Patients undergoing interventional surgical or radiological procedures, or receiving targeted therapies were excluded. In all patients, target lesions were identified on baseline MRI scans, and assessed on follow-up scans according to the RECIST criteria. Among 67 PROS patients screened from 2008 to 2021, 30 met the inclusion criteria, including 43.3% female patients. The median age at first MRI was 19 years (interquartile range, 5 to 34) and the median interval between the two scans was 75.7 months (range, 2.1 to 160.3 months). Recurrent localizations included the face (n = 6; 20%), ear, nose and throat region (n = 3; 10%), upper limbs (n = 5; 16.7%), thorax (n = 3; 10%), abdomen (n = 4; 13.3%), pelvis (n = 5; 16.7%), and lower limbs (n = 10; 33.3%), with some patients presenting multisite involvement. During the observation period, 86.6% (n = 26) of patients exhibited an increase in target lesion volume, with a median progression of 37.8% (range, 2.6 to 233.0%) and a mean progression of 52% (standard error of the mean, 7.2%), reflecting a right-skewed distribution driven by a subset of rapidly enlarging lesions. In conclusion, this study provides the first radiological description of the natural history of PROS, demonstrating that tissue malformations most often enlarge over time, with sustained progression persisting into adulthood.