Macrosomia, transient neonatal hypoglycemia, and monogenic diabetes in a family with heterozygous mutation R154X of HNF4A gene

252 Congenital hyperinsulinemic hypoglycemia (CHI) is a potentially life-threatening condition which is often caused by loss-of-function mutations in ABCC8 and KCNJ11 genes, that encode for the ATP-sensitive potassium channel of the pancreatic β cell. Recently, it has been shown that in families with monogenic diabetes due to genetic defects of the transcription factor HNF4A [known as Maturity Onset Diabetes of the Young type 1 (MODY1)] mutation carriers can present neonatal hypoglycemia and macrosomia (1). Here we report about a girl born large for gestational age, who showed severe neonatal hypoglycemia (day 1 of life) treated with glucose infusion (Table 1). She had a second hypoglycemic episode at day 9, treated again with glucose infusion for 2 days. Her younger sister, who was delivered by cesarean section because of macrosomia and polyhydramnios at 34 weeks of gestation, also presented with mild, transient neonatal hypoglycemia. Both were referred to us for molecular genetic screening. Family history disclosed early-onset Type 2 diabetes in the mother and in the maternal grandfather. In particular, the mother had been diagnosed with gestational diabetes – treated with insulin – during her second pregnancy (35 yr of age) and, after a year free of therapy, started on oral hypoglycemic agents. These data combined prompted us to screen directly the HNF4A gene in this family. We identified a C>T substitution at position 460 (c.460C>T), resulting in the already described mutation arginine→stop at codon 154 (p.R154X) (Table 1) in the proband, her sister, and her mother. DNA of maternal grandfather, deceased, was not available. The proband, now almost 15 yr old (pubertal stage: Ph5,B5), and a bit overweight, has shown at the last visit above normal glycated hemoglobin value compatible with recently proposed criteria for diagnosis of diabetes (2). This finding is in line with what is usually seen in patients with heterozygous mutations of HNF4A gene or TCF1/HNF1A (so-called MODY 3), who present with diabetes at adolescence or as young adults.