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. 2024 Aug 13;109(9):2349-2357.
doi: 10.1210/clinem/dgae095.

The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022

Novella Rapini  1 , Maurizio Delvecchio  2   3 , Mafalda Mucciolo  4 , Rosario Ruta  4 , Ivana Rabbone  5 , Valentino Cherubini  6 , Stefano Zucchini  7 , Stefano Cianfarani  8   9   10 , Elena Prandi  11 , Riccardo Schiaffini  8 , Carla Bizzarri  8 , Barbara Piccini  12 , Giulio Maltoni  7 , Barbara Predieri  13 , Nicola Minuto  14 , Rossella Di Paola  15 , Mara Giordano  16   17 , Nadia Tinto  18 , Valeria Grasso  19 , Lucia Russo  19 , Valentina Tiberi  6 , Andrea Scaramuzza  20 , Giulio Frontino  21 , Maria Cristina Maggio  22 , Gianluca Musolino  23 , Elvira Piccinno  2 , Davide Tinti  24 , Paola Carrera  25   26 , Enza Mozzillo  27 , Marco Cappa  28 , Dario Iafusco  29 , Riccardo Bonfanti  30 , Antonio Novelli  4 , Fabrizio Barbetti  1 ; Diabetes Study Group of Italian Society for Pediatric Endocrinology and Diabetes (ISPED)
Collaborators, Affiliations

The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022

Novella Rapini et al. J Clin Endocrinol Metab. .

Abstract

Context: In the last decade the Sanger method of DNA sequencing has been replaced by next-generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM).

Objective: To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) vs 2013-2022 (NGS).

Methods: We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM + c.SIR) of the Italian dataset.

Results: Fifty-five patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103 340 (NDM) and 1:1 240 082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, P = .034 vs 2003-2012). Notably, among rare genes 5 were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA) were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes, and the individual with lipodystrophy caused by BSCL2 was started on metreleptin.

Conclusion: NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and c.SIR in Italy.

Keywords: autoimmune neonatal diabetes mellitus; congenital severe insulin resistance; molecular genetics; monogenic diabetes; neonatal diabetes mellitus.

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Figures

Figure 1.
Figure 1.
Genetic etiology of PNDM in the period 2003-2012 compared with the period 2013-2022.
Figure 2.
Figure 2.
Genetic etiology of TNDM in the period 2003-2012 compared with the period 2013-2022.
Figure 3.
Figure 3.
Estimated incidence of NDM in different countries. References concerning incidence in individual countries: Poland (28), Slovakia (29), United States (30), Jordan (31), Qatar (32), Saudi Arabia (33), Turkey (34), United Arab Emirates (35).
See this image and copyright information in PMC

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