title: Testing for monogenic diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes.
abstract: OBJECTIVE
  Monogenic diabetes is frequently misdiagnosed as Type 1 diabetes. We aimed to screen for undiagnosed monogenic diabetes in a cohort of children who had a clinical diagnosis of Type 1 diabetes but were pancreatic autoantibody-negative.
  
  
  METHODS
  We studied 252 patients diagnosed clinically with Type 1 diabetes between 6 months and 17 years of age. Pancreatic autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and/or insulinoma-associated antigen-2 antibodies (IA2A)] were absent in 25 cases (9.9%). The most frequent genes involved in monogenic diabetes [KCNJ11 and INS for neonatal diabetes and HNF1A and HNF4A for maturity-onset diabetes of the young (MODY)] were directly sequenced.
  
  
  RESULTS
  Two of the 25 (8%) antibody-negative patients had de novo heterozygous mutations in INS; c.94G>A (G32S) and c.265C>T (R89C). The two patients presented with non-ketotic hyperglycaemia at 8 and 11 months of age. In contrast, the four antibody-positive patients who presented at a similar age (6-12 months) had a more severe metabolic derangement, manifested as ketosis in all four cases, with ketoacidosis in two. At ages 15 and 5 years, both INS mutation patients were prescribed a replacement dose of insulin with good glycaemic control [glycated haemoglobin (HbA(1c)) 7.0 and 7.2%]. No mutations were found in KCNJ11, HNF1A or HNF4A.
  
  
  CONCLUSIONS
  The identification of patients with monogenic diabetes from children with clinically defined Type 1 diabetes may be helped by clinical criteria including the absence of pancreatic autoantibodies.
authors.affiliation: Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain. oscar.rubio-cabezas@pms.ac.uk
authors.forename: O
authors.initials: O
authors.lastname: Rubio-Cabezas
authors.forename: E L
authors.initials: EL
authors.lastname: Edghill
authors.forename: J
authors.initials: J
authors.lastname: Argente
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000293:Adolescent; D000906:Antibodies / Q000235:genetics*; D001323:Autoantibodies / Q000097:blood*; D001786:Blood Glucose / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007328:Insulin / Q000235:genetics*; D008297:Male
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin