ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2017) 51 P067 | DOI: 10.1530/endoabs.51.P067

Siblings with monogenetic ABCC8 diabetes - phenotypic variability and implications

Charlotte Jackson, Murray Bain & Christina Wei

St George’s University Hospital NHS Foundation Trust, London, UK.

Introduction: ABCC8 gene mutations cause transient and permanent forms of neonatal diabetes with variable modes of inheritance. Almost all patients present with diabetes under 6 months old with rare cases upto 12 months. We report 2 siblings with diabetes and identical homozygous mutations of the ABCC8 gene, one of whom presented classically under 6 months old and the other unusually at 3 years of age.

Cases: The index case, a British Pakistani female, was diagnosed with diabetes aged 3 years following investigation for recurrent napkin dermatitis. She presented with elevated blood glucose (20.3 mmol/l), glycosuria (4+) and HbA1C of 102 mmol/l, but was not in diabetic ketoacidosis (DKA). Her parents are first cousins and there was no family history of diabetes. She was born at term, weighing 3.3 kg, with no other significant past medical history. Her physical examination was normal and she was not obese. A presumptive diagnosis of Type 1 diabetes was made and basal bolus insulin regime was initiated. Subsequent results of islet cell and glutamic acid decarboxylase antibodies were negative. Three months later, her brother was born at term, weighing 2 kg. At 10 weeks age he presented with loose stools, weight loss, and DKA (pH 7.27, base excess −11, glucose 60 mmol/l). He was treated according to the DKA protocol and then transferred to daily intermediate-acting subcutaneous insulin. Genetic analysis (Exeter Genetics Service) of both siblings subsequently demonstrated identical homozygous missense mutation (c.320T>A) at exon 26 for the ABCC8 gene encoding SUR subunit of KATP channels on pancreatic beta cells. Both siblings were then switched from subcutaneous insulin to oral glibenclamide with continuation of target glycaemic control (HbA1c <38 mmol/mol).

Conclusions: Mutation analysis for neonatal diabetes is currently offered to all infants diagnosed with diabetes under 9 months old. Without the classic presentation of the younger sibling, genetic analysis for ABCC8 would not have been undertaken so promptly. The criteria for genetic screening in children with diabetes from consanguineous family needs consideration. The different presentations between the siblings with the same mutation emphasises the difficulties with genotypic–phenotypic correlations that can occur in monogenetic diabetes.

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