ESPE Abstracts

Introduction: Mendelian diseases are rare individually but collectively are estimated to affect more than 5% of global population with more than 6000 different rare phenotypes including monogenic forms of diabetes. The proportion of individuals who possess a particular genotype and exhibit the expected phenotype is defined as the penetrance of that genotype. If everyone with the genotype presents with clinical symptoms by a particular age, then it is said to be fully penetrant, whereas if it falls below this, it is said to exhibit reduced or incomplete penetrance. Often Mendelian diseases have incomplete penetrance. Mutations in the genes ABCC8, KCNJ11, and INS are the common causal genes for neonatal diabetes mellitus (NDM) and all three may also cause MODY phenotype. We report a unique case of NDM which highlights this phenomenon.

Case presentation: 3-month-old female, second child of non-consanguineous parentage, born at full term by normal vaginal delivery presented with severe diabetic ketoacidosis (DKA). On presentation to the emergency room the Glasgow coma scale was 3, blood glucose was 31mmol/L, beta hydroxy butyrate was 5.2mmol/L and Hba1c 12.5%. She required intubation and mechanical ventilation. The working diagnosis was probable NDM considering the age of onset presenting in severe DKA. She was discharged on Detemir 2 units and bolus insulin Lispro 0.5 units pre feeds. The Hba1c after 1.5 months was 6.2% and was off insulin completely. She was on Dexcom G6 glucose sensor for continuous glucose monitoring which showed time in range (TIR%) 61% and then on further follow up 91%. Using whole genome sequencing of the affected proband we found that our patient and her mother have a heterozygous variant in ABCC8 gene (variant identified was c.4136G>T, p.Arg1379Leu). The father and healthy sibling was negative for this finding. Subsequently the mother was evaluated with random blood sugar and HbA1c and was found to be normoglycemic. Currently our patient is 9 months old, with normal developmental milestones for age and is off insulin since the past 5 months with an HbA1c of 5.5%

Conclusion: This case highlights the phenomenon of incomplete penetrance and variable expressivity in monogenic forms of diabetes. The variant detected in the proband is rare across the databases. Our patient and her mother carried the same heterozygous variant in ABCC8 gene. This led to the child having transient neonatal diabetes, however mother was asymptomatic which highlights the incomplete penetrance and variable expression of the genotype.