Abstract Background In very early onset inflammatory bowel disease (VEOIBD), defined as IBD araising before the age of 6 years, monogenic forms are typically associated with severe clinical manifestations and often require targeted or intensive therapies. Yet these monogenic etiologies account for only 8–13% of cases. In the much larger group with non-monogenic VEOIBD (nm-VEOIBD), prognosis at diagnosis remains uncertain, and the factors that drive disease severity and long-term progression are still poorly understood. We aimed to describe the clinical course of nm-VEOIBD and identify baseline variables associated with a severe disease trajectory. Methods In a multicenter retrospective study, children diagnosed with nm-VEOIBD and followed for at least 5 years were included. Baseline demographic and clinical characteristics were compared between patients with severe and non-severe disease courses, defined according to patterns of disease activity over time. Results A total of 128 nm-VEOIBD patients were included: 30 with Crohn’s disease and 98 with ulcerative colitis or IBD-undetermined. Median age at diagnosis was 33 months (IQR 14–53), and median follow-up was 10 years (IQR 7–13). A severe disease course was observed in 50 patients (38%). At diagnosis, children who later developed a severe trajectory more often exhibited growth delay (42% vs. 21.8%, p = 0.02) and a severe phenotype (46% vs. 21.8%, p = 0.01). No significant differences were found in demographic features, disease phenotype, or initial hematologic parameters. Conclusion In this large nm-VEOIBD cohort, nearly one third of patients experienced a severe disease course. Growth delay and a severe phenotype at diagnosis were the only baseline variables more frequently associated with a severe trajectory, underscoring their potential value in early risk stratification. Conflict of interest: Dr. Lega, Sara: No conflict of interest Ferra, Veronica: No conflict of interest Longo, Chiara: No conflict of interest Alvisi, Patrizia: No conflict of interest Morello, Rossella: No conflict of interest Scarallo, Luca: No conflict of interest Sola, Alessandro: No conflict of interest Angelino, Giulia: No conflict of interest Hojsak, Iva: Personal Fees: BioGaia, Biocodex, Abbott, Sandoz, Takeda, Ewopharma, Hipp, GM Pharma Oliva, Salvatore: No conflict of interest Gianolio, Laura: No conflict of interest Tizi, Fatima: No conflict of interest De Angelis, Paola: No conflict of interest Zuin, Giovanna: No conflict of interest Lionetti, Paolo: No conflict of interest Romano, Claudio: No conflict of interest Arrigo, Serena: No conflict of interest Bramuzzo, Matteo: No conflict of interest
Lega et al. (Thu,) studied this question.