Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy

in European Journal of Endocrinology
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  • 1 Department of Pediatrics, Pediatric Diabetology Unit, Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
  • | 2 Department of Pediatrics, University of Campania Luigi Vanvitelli, Naples, Italy
  • | 3 Department of Pediatrics, University of Turin, Turin, Italy
  • | 4 Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
  • | 5 Diabetology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
  • | 6 S. Maurizio Hospital, Bolzano, Italy
  • | 7 Department of Pediatrics, University of Rome Sapienza, Rome, Italy
  • | 8 Department of Internal Medicine and Therapeutics, Pediatric and Adolescent Unit, University of Pavia and Department of Pediatrics, ‘Vittore Buzzi’ Children’s Hospital, Milan, Italy
  • | 9 Department of Medical and Surgical Sciences of Mother, Children and Adults, Pediatric Unit, University of Modena and Reggio Emilia, Modena, Italy
  • | 10 SCDU of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, Novara, Piemonte, Italy
  • | 11 Department of Pediatrics, S. Maria degli Angeli Hospital, Pordenone, Italy
  • | 12 Regional Center for Pediatric Diabetes, Giovanni Di Cristina Children Hospital, Palermo, Italy
  • | 13 Regional Center for Pediatric Diabetes, AOU, Policlinico Vittorio Emanuele, Catania, Italy
  • | 14 Regional Center for Pediatric Diabetes, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  • | 15 Great Metropolitan Hospital BMM, Reggio Calabria, Italy
  • | 16 Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
  • | 17 Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
  • | 18 Regional Center for Pediatric Diabetes, Meyer University Children’s Hospital, Florence, Italy
  • | 19 San Raffaele Scientific Institute, Center for Omics sciences @OSR, Genomics for the Diagnosis of Human Pathologies, Milan, Italy
  • | 20 San Raffaele Scientific Institute, Laboratory of Molecular Genetics and Cytogenetics, Milan, Italy
  • | 21 Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children’s Hospital, Bari, Italy

Correspondence should be addressed to F Barbetti; Email: fabrizio.barbetti@uniroma2.it

*(R Bonfanti, D Iafusco and I Rabbone contributed equally to this work)

**(Details of the Diabetes Study Group of ISPED is given in the Acknowledgements section)

(I Rabbone is now at Department of Pediatrics, University of Piemonte Orientale, Novara, Italy)

(L Russo is now at University of Michigan, Ann Arbor, Michigan, USA)

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Objective

Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features.

Design

Retrospective analysis of the Italian data set of patients with 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 values, 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 KATP/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 diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP 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 with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Supplementary Materials

    • Supplemental Table 1 R Bonfanti_ACMG score of new variants

 

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