DOI: 10.4274/jcrpe.galenos.2019.2019.0106 case report Heterozygous Insulin Receptor (INSR) Mutation associated with Neonatal Hyperinsulinemic Hypoglycaemia and Familial Diabetes Mellitus: Case Series Sethi A et al. INSR mutation and Neonatal Hyperinsulinemic Hypoglycaemia Aashish Sethi 1 , Nicola Foulds 2 , Sarah Ehtisham 3 , Syed Haris Ahmed 4 , Jayne Houghton 5 , Kevin Colclough 5 , Mohammed Didi 1 , Sarah E. Flanagan 6 , Senthil Senniappan 1 1 Department of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK 2 Clinical Genetics, Wessex Clinical Genetics Services, Southampton, UK 3 Deparment of Paediatric Endocrinology, Mediclinic City Hospital, Dubai, UAE 4 Department of Endocrinology, Countess of Chester Hospital, Chester, UK 5 Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 6 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK Abstract Mutations in the insulin receptor (INSR) gene are associated with insulin resistance and hyperglycaemia. Various autosomal dominant heterozygous INSR mutations leading to hyperinsulinemic hypoglycaemia (HH) have been described in the adults and children (more than 3 years of age) but not in the neonatal period. Family 1: A small for gestational age (SGA) child born to a mother with gestational diabetes presented with persistent hypoglycaemia, was diagnosed with HH and responded well to diazoxide treatment. Diazoxide was gradually weaned and discontinued by 8 months of age. Later, the younger sibling had a similar course of illness. On genetic analysis a heterozygous INSR missense variant p.(Met1180Lys) was found in the siblings, mother and grandfather but not in the father. Family 2: A twin preterm and SGA baby presented with persistent hypoglycaemia, which was confirmed as HH. He responded to diazoxide, which was subsequently discontinued by 10 weeks of life. Genetic analysis revealed a novel heterozygous INSR missense variant p.(Arg1119Gln) in the affected twin and the mother. Family 3: A SGA child presented with diazoxide responsive HH. Diazoxide was gradually weaned and discontinued by 9 weeks of age. Genetic analysis revealed a novel heterozygous INSR p.(Arg1191Gln) variant in the proband and her father. We report, for the first time, an association of INSR mutation with neonatal HH responsive to diazoxide therapy that resolved subsequently. Our case series emphasizes the need for genetic analysis and long-term follow up of these patients. Keywords: INSR mutation, congenital hyperinsulinism, neonatal hyperinsulinemic hypoglycaemia, familial diabetes mellitus *Corresponding Author: Dr. Senthil Senniappan, Consultant Paediatric Endocrinologist and Senior Lecturer, Department of Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, L14 5AB, UK Tel: 01512525281 Email: senthilkss@yahoo.co.uk ORCID ID: https://orcid.org/0000-0002-8001-034 Submitted: 06-Aug-2019 Accept: 21-Nov-2019 Introduction: Insulin receptor is a trans-membrane receptor from tyrosine kinase family where insulin binds to two distinct sites on each subunit of the receptor (1, 2). Insulin receptor mutations are associated with severe insulin resistance phenotypes, such as Rabson-Mendenhall, Donohue and type A insulin resistance syndrome (3, 4). Rabson-Mendenhall and Donohue syndromes are recessively inherited conditions leading to decreased expression of receptor, blockage of receptor transport to the plasma membrane or decreased insulin binding, associated with extreme insulin resistance. Type A insulin resistance is associated with mono allelic INSR missense mutations, which cause a less severe phenotype and are most likely to occur within the tyrosine kinase domain (4). Insulin is an anabolic peptide hormone secreted by the beta cells of pancreatic islets. Inappropriate secretion of insulin leads to persistent/recurrent hypoglycaemia (hyperinsulinemic hypoglycaemia, HH), which can result from a mutation in a number of different genes (5, 6). uncorrected proof