GCK Mutation in a Child with Maturity Onset Diabetes of the Young, Type 2
A 9-year-old boy from northern Iran was referred to the Children's Medical Center, the Pediatrics Center of Excellence in Tehran-Iran, for evaluation of high fasting plasma glucose. He was from unrelated parents, and his mild hyperglycemia has been accidentally discovered a few months before during routine laboratory tests. He did not have polydipsia and polyuria, neither any weight loss.\nOn examination, he was well and healthy, weight and height 43 kg and 148 cm respectively (>97th percentile of Iranian boys of corresponding age) with body mass index (BMI) of 24 kg/m2. He had no acanthosis nigricans. Fasting blood sugar (FBS) 114 mg/dL, HbA1c 6.5%. A standard oral glucose tolerance test (OGTT) with 75g of glucose equivalent was performed with a fasting glucose of 125 mg/dL and 2-hour glucose of 133 mg/dL. Fasting insulin concentration was 7.5 µIU/mL. No glucosuria or ketonuria were detected. Further investigations revealed normal liver function test, lipid profile, and abdominal ultrasound. In addition, the pancreatic islet cell autoantibodies (ICA) and glutamic acid decarboxylase autoantibodies (GADA) were negative. Both clinical presentation and laboratory data were highly suggestive of a GCK mutation.\nFamily history disclosed a diagnosis of diabetes mellitus in his paternal grandmother 10 years ago, at the age of 55 years, but she took no medication. Because there was no history of diabetes in his parents, evaluation was performed. The mother was healthy, with FBS of 88 mg/dL and blood glucose of 94 mg/dL at 120’ of OGTT. Instead, the 41-year-old father had an FBS of 115 mg/dL and his blood glucose was 162 mg/dL at 2-hours after GTT; his weight was 95 kg, his height 185 cm, with a resulting BMI of 27.9 kg/m2. These findings showed that diabetes or IFG/IGT was present in three consecutive generations in this family and reinforced the clinical diagnosis of MODY, type 2.\nConsequently, after getting written informed consent, direct DNA sequencing of all exons and intron-exon bounders of the GCK gene was performed on patient's genomic lymphocytes DNA, which showed a heterozygous single nucleotide deletion in exon 8 (c.1010delA) causing a frame-shift with the formation of a premature stop codon (TGA) downstream at codon 352 (exon 9) (). The same mutation was found in his father as well. Therefore, the diagnosis of MODY2 was confirmed in the family.\nConsequently, after getting written informed consent, direct DNA sequencing of all exons and intron-exon bounders of the GCK gene was performed on patient's genomic lymphocytes DNA, which showed a heterozygous single nucleotide deletion in exon 8 (c.1010delA) causing a frame-shift with the formation of a premature stop codon (TGA) downstream at codon 352 (exon 9) (). The same mutation was found in his father as well. Therefore, the diagnosis of MODY2 was confirmed in the family.\nSerial blood glucose measurements in the patient obtained by glucometer at home showed variable fasting readings ranging between 115 mg/dL and 155 mg/dL; fasting insulin concentration was 6.4 µIU/mL, HbA1c was 6.6%. A second OGTT showed blood glucose of 117, 134, 128, and 118 mg/dL at 0, 60, 120, 180 minutes, respectively, confirming a non-progressive, mild alteration of glucose metabolism. The patient received some dietary advices and no medication and a follow-up appointment in the diabetes clinic. His last biochemical tests after 4 months showed FBS of 127 mg/dL. His latest HbA1c was 6.4%. We recommended further dietary restriction and regular follow-up.