A case series of maturity onset diabetes of the young: Searching for a polar bear in a snowstorm

INTRODUCTION

Monogenic diabetes occurs due to a defect in a single gene or a chromosomal locus. The various modes of inheritance occurring include autosomal recessive, autosomal dominant, non-Mendelian traits or can occur as a spontaneous case secondary to a de novo mutation. The most commonly recognised forms of diabetes mellitus include the polygenic forms of diabetes, such as type 1 or type 2 diabetes. Although uncommon, monogenic diabetes accounts for 2.5–6% of diabetes in the paediatric age group^[1] and usually presents under 25 years of age. Monogenic diabetes can be classified into four major groups: (1) Maturity onset diabetes of the young (MODY), (2) neonatal and early infancy diabetes, (3) monogenic insulin resistance syndromes, and (4) diabetes affiliated with extra-pancreatic features.^[1] MODY is the most prevailing form of monogenic diabetes with an autosomal dominant inheritance. There are 14 subtypes of MODY that have been recognised now, and mutations in the genes hepatic nuclear factor 1-alpha (HNF1α) (MODY-3), glucokinase (MODY-2) HNF4α (MODY-1) account for about 95% of all MODY cases [Table 1].^[2] Through this case series, we aim to report rarer forms of MODY and present a comparison of their various characteristics in terms of their presentation and management.

CASE SERIES

DISCUSSION

The acronym ‘MODY’ was coined by Fajans and Tattersall in 1974, who defined it as ‘fasting hyperglycaemia’.^[3] MODY occurs due to impaired insulin secretion due to a defect in the development of pancreatic islet cells. The genes implicated in MODY hamper insulin secretion by impairment of insulin sensing, glucose metabolism in beta-cells of the pancreas, or activation of adenosine tri-phosphate-dependent potassium channels.^[4] According to a study in the UK, 80% of MODY cases are misdiagnosed as one of the polygenic forms of diabetes, either T1DM or T2DM, as they have overlapping genotypic features of both. Vaxillaire and Froguel determined the major diagnostic criteria for MODY to be hyperglycaemia before 25 years of age, autosomal dominant inheritance exhibiting transmission in at least three generations, negative beta-cell autoantibodies, and functional impairment in the pancreatic beta-cells.^[5,6] In our case series, we report four cases of MODY and compare their various characteristics. A genetic test was performed for children and adolescents with diabetes mellitus who had a strong history of diabetes in the family and tested negative for islet cell antibodies. Genetic counselling was done in view of the autosomal dominant fashion of inheritance.^[6] Management differs among the various types of MODY, where some respond to lifestyle modifications, and some require insulin or oral antidiabetic drugs or a combination of both.^[7]

CONCLUSION

Although there have been cases of MODY that have been previously reported worldwide, they usually fall under the types – MODY-3 (30–50% cases), MODY-2 (15–25% cases), and MODY-1 (5%), whereas all the other types of MODY contribute to <1% of the cases individually. In our case series, we identified one adolescent with KLF-11 gene mutation giving rise to MODY-7 and two adolescents with PAX-4 gene mutation causing MODY-9, both of which contribute to <1% of the cases of MODY reported worldwide. As MODY shares features of the more commonly encountered forms of diabetes, such as T1DM and T2DM, we often miss identifying MODY. Hence, the phrase ‘searching for a polar bear in a snowstorm’ aptly applies to identifying MODY cases among the numerous cases of type 1 and type 2 diabetes.