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Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activa ting mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We want ed to assess whether these different genetic aetiologies result in distinct clinical features. Design: Retrospective analysis of the Italian data set of patients wit h TNDM. Methods: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose value s, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in K ATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal di abetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with K ATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients w ith macroglossia and/or umbilical hernia. Remission of diabetes without pharmaco logical therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remis sion of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy. [ABSTRACT FROM AUTHOR]