Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing type 1 diabetes mellitus.

BACKGROUND: Incidental hyperglycemia in children generates concern about the presence of preclinical type 1 diabetes mellitus (T1DM). OBJECTIVE: To genetically evaluate two common forms of maturity-onset diabetes of youth (MODY), the short-term prognosis in children with mild hyperglycemia, and a positive family history of diabetes mellitus. SUBJECTS: Asymptomatic children and adolescents (n = 14), younger than 15 yr, with fasting hyperglycemia, a positive family history of mild non-progressive hyperglycemia, and negative pancreatic autoantibodies were studied. PATIENTS AND METHODS: Glucokinase gene (GCK) and hepatocyte nuclear factor 1 alpha gene (HNF1A) causing two common forms of MODY were sequenced. The clinical outcome was evaluated after a follow-up period of 2.8 +/- 1.3 yr. RESULTS: GCK mutations were present in seven children. The confirmation of this diagnosis allowed discontinuation of insulin in two families and oral medications in three families. Mutations of HNF1A were not detected in any of the families. During the follow-up period, all the GCK mutation carrier children remained asymptomatic without medication and the last hemoglobin A1c levels were 6.4 +/- 0.7%. In the GCK-negative children (n = 7), one developed T1DM, corresponding to 7.2% of the total group. Mild fasting hyperglycemia persisted during follow-up in four GCK-negative children and normalized in the remaining two. CONCLUSIONS: The presence of mild persistent hyperglycemia in any patient without autoantibodies should lead to genetic analysis of GCK, particularly if there is a positive family history. Furthermore, those without GCK mutations should be followed with repeat autoantibody testing, and other genetic types of diabetes should be considered if hyperglycemia worsens.

Glucokinase mutations in young children with hyperglycemia.

BACKGROUND: The etiology of mild hyperglycemia without ketoacidosis in young children is often unknown. Maturity onset diabetes of youth (MODY) is a form of diabetes mellitus (DM) characterized by fasting hyperglycemia without evidence for autoimmune destruction of beta-cells. METHODS: We genetically analyzed four families of young children with fasting hyperglycemia with family histories of diabetes for mutations in the genes for hepatocyte nuclear factor 4 alpha (HNF4alpha), glucokinase (GCK), and hepatocyte nuclear factor 1 alpha (HNF1alpha), the genes responsible for MODY1, MODY2, and MODY3, respectively. RESULTS: We identified mutations in GCK (Gly258Asp, Arg303Trp, and Arg191Gln) in three of the four families. Molecular genetic characterization in these children clarified the etiology and prognosis of the hyperglycemia and allowed discontinuation of insulin therapy in one family. CONCLUSIONS: We conclude that molecular evaluation for MODY in children with mild fasting hyperglycemia without ketosis with family histories of diabetes can provide important prognostic information to guide therapy and exclude preclinical type 1 diabetes mellitus.