Endocrine Abstracts

Background: Mutations in the insulin receptor (INSR) gene are rare and cause a spectrum of severe insulin resistance syndromes including Donohue syndrome, Rabson Mendenhall syndrome, and Type A Insulin Resistance Syndrome (IRS). We describe a young female with a heterozygous INSR mutation, who presented with antibody positive diabetes mellitus (DM) and subsequently developed features of Type A IRS.

Case Report: A 12 year old Jamaican girl with a BMI of 25 kg/m² presented with polyuria, polydipsia and hyperglycaemia (blood glucose 18 mmol/l). HbA1c was raised at 85 mmol/mol, urinary ketones were negative. Antibodies to islet antigen-2 were positive (0.56 U/ml; normal range: 0–0.35 U/ml), and antibodies to glutamic acid decarboxylase and insulin were negative. She was diagnosed with Type 1 DM and started on a basal-bolus insulin regime. She previously had precocious puberty, treated with GnRH analogues. She achieved menarche at 13 years with irregular cycles. Over 2 years, she developed hirsutism, acanthosis nigricans, and postprandial hypoglycaemia, with no evidence of lipodystrophy. Biochemical investigations showed raised serum C-peptide (854 pmol/l), LH (29.1 IU/l), and testosterone levels (3.6 nmol/l), with normal lipids. Ultrasound pelvis revealed enlarged ovaries with multiple peripheral follicles suggestive of PCOS. Family history included DM affecting mother, maternal uncle and maternal grandfather. Targeted next generation sequencing of the monogenic diabetes genes revealed a heterozygous missense INSR variant p.(His1157 Gln), c.3471T>G in the patient and affected mother. The p.His1157 residue is present within the catalytic loop of the tyrosine kinase domain of the INSR. A different missense variant affecting the same residue, p.(His1157Arg), has been previously associated with Type A IRS. The patient was started on metformin and weaned off insulin therapy. Her menstrual cycles then normalised and glycaemic control improved (HbA1C 36 mmol/l).

Conclusion: This is a novel description of a p.His1157Gln mutation in INSR causing Type A IRS. Our findings highlight the role of puberty in the manifestation of insulin resistance. This case also emphasises the importance of exploring an INSR defect in slim patients with DM and features of insulin resistance in the absence of lipodystrophy and normal lipids.