ESPE Abstracts

Introduction: Early onset diabetes mellitus (DM) presents a challenge in pediatric clinical settings, often necessitating comprehensive genetic investigation to understand underlying causes and tailor management strategies. This study aimed to elucidate the genetic basis of early onset DM through whole exome sequencing and assess its clinical relevance.

Methods: Between July 2022 and May 2024, we conducted a prospective study at CNU Sejong Hospital, enrolling 34 unrelated patients (19 males, 15 females) aged 1 month to 18 years, diagnosed with type 2 DM or type 1B DM. The cohort included 2 patients with neonatal DM, 7 patients with type 1B DM, and 25 patients with type 2 DM. Clinical characteristics were documented, including HbA1c levels, presence of diabetes-related antibodies, acanthosis nigricans, and family history. Whole exome sequencing was performed, and identified variants in diabetes-related genes were assessed. Clinical significance was evaluated through parental and sibling tests.

Results: Patients exhibited a mean HbA1c of 10.5 ± 2.4% at diagnosis and were negative for anti-GAD, anti-insulin, and anti-islet antibodies. No pathogenic mutations related to DM were detected in patients with type 1B DM. Twenty-eight patients (82.4%) had a family history of DM, and 17 variants were identified in diabetes-related genes, including FOXP3, GCK, IRS1, ABCC8, INSR, WFS, KLF11, SLC2A4, HNF1B, PPARG, and MT-TE. Remarkably, 15 out of the 17 patients with genetic variants had positive family histories. Four GCK variants were identified in both neonatal and adolescent cases, all with familial connections. Variants in IRS1, ABCC8, INSR, WFS, KLF11, SLC2A4, HNF1B, PPARG, and MT-TE were observed in type 2 DM patients, reinforcing susceptibility. Patients with FOXP3, WFS1, and MT-TE mutations required further evaluation for other organ involvement and cautious genetic counseling for affected families. Notably, a FOXP3 variant was discovered in a preterm neonate with hyperglycemia, evolving into neonatal diabetes. This case transitioned into IPEX syndrome, leading to a bone marrow transplant. For patients with GCK mutations, we could explain the prognosis and future management without unnecessary treatment and work-up. Patients with HNF1B mutations required insulin treatment and monitoring for renal and extra-renal disease.

Conclusion: This study demonstrates the utility of genetic diagnosis in managing early onset diabetes among pediatric patients. Comprehensive genetic investigation enhances our understanding of diabetes etiology, provides insights into clinical trajectories, and informs patient management decisions. Early genetic diagnosis holds promise for personalized care and improved outcomes in pediatric diabetes cases.