Endocrine Abstracts

Introduction

’Maturity-onset diabetes of the young’ (MODY) constitutes a group of clinically and genetically heterogeneous monogenic forms of diabetes, characterized by beta-cell dysfunction. It describes an autosomal dominantly inherited disorder, caused by mutations in different genes, characterized by noninsulin-dependent diabetes commonly diagnosed at a young age. Fourteen MODY subtypes have been reported, often misdiagnosed as type 1 or 2 diabetes.

Aim

To present a male suspected for MODY, who was tested molecularly using the Next Generation Sequencing (NGS) for 7 MODY genes (GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8 and KCNJ11).

Case description

A 17-year-old male presented after laboratory investigation indicating hyperglycemia (glucose: 281 mg/dl). He complained for polyuria, polydipsia and weight loss (~ 4 kg) in the last month. On admission, he had glucose: 391 mg/dl without acidosis, HbA1c: 10.4%, normal BMI (18.7 kg/m²) and negative pancreatic auto-antibodies. Urinary protein excretion was elevated (205 mg/day). There was no family history of diabetes. He was initially treated with insulin, which was gradually decreased and finally discontinued within a month. Three months later his HbA1c was 7.2% and insulin treatment was implemented again due to poor glycemic control. Genetic analysis revealed that he was heterozygous for a novel p.V21F variant of the ABCC8 gene (exon 1, c.61G > T, of paternal origin) and for the p.A98V variant of the HNF1A gene (exon 1, c.293C > T, of maternal origin). p.V21F variant is reported for the first time and is classified as likely pathogenic, while p.A98V is classified as likely benign. Once the mutation was identified, the patient switched to gliclazide, which was eventually replaced by insulin as hyperglycemia was not successfully controlled with sulfonylurea alone (HbA1c after 3 months of treatment increased to 7.6%). Genetic investigation in both parents revealed that the father was heterozygous for the same ABCC8 p.V21F likely pathogenic variant, but asymptomatic. The HNF1A variant was inherited from the mother.

Conclusions

Given the different therapeutic approach and the complications risk depending on the diabetes form, a correct diagnosis and optimal treatment is essential for a good prognosis and appropriate genetic counseling. This case emphasizes the need of considering molecular analysis, even in the absence of a family history of diabetes if clinical suspicion for MODY is high. A novel likely pathogenic variant of the ABCC8 gene is described, which refers to subtype MODY 12 and cannot be successfully treated with sulfonylurea monotherapy, as generally suggested (1).

References

1. Reilly F. et al. Diabet Med. 2020;37(5):876–84.