HH is linked to mutations in at least eight genes ( ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A) that alter β-cell function ( 7). HH infants have inappropriate insulin and/or C-peptide levels despite the presence of hypoglycemia, hypoketonemia and hypofattyacidemia. Hyperinsulinemic hypoglycemia (HH) is characterized by inappropriate insulin secretion while hypoglycemic and the need for high glucose infusion rate (GIR) requirements (>8 mg/kg/min) to maintain normoglycemia (3.5–5.9 mmol/L) in newborn infants beyond 48 h of life. The prevalence of neonatal hypoglycemia is similar regardless of parental HNF4A inheritance and persistent hypoglycemia is independent of gestational glucose control ( 6). Among infants with HNF4A mutations, 56% are macrosomic and 15% encounter neonatal hypoglycemia ( 5). HNF4A mutations are a less common cause of MODY (10%) than glucokinase (GCK) (30–50%) and HNF1A (30–50%). Mutations in HNF4A may lead to biphasic presentations, characterized by transient or persistent HH in infants, and diabetes in young adults. HNF4A is an orphan receptor protein expressed in the liver, kidney, gut, and pancreatic β-cells ( 4). Among these, only HNF4A (MODY1) and HNF1A (MODY3) mutations on chromosomes 12 and 20 respectively, may result in a biphasic phenotype ( 3). MODY gene mutations have been described with clinically heterogeneous phenotypes ( 2). Maturity-onset diabetes of the young (MODY) is an acronym used to describe dominantly inherited forms of monogenic diabetes diagnosed before 25 years of age ( 1). This pedigree suggests that the presence of early-onset paternal diabetes should prompt molecular testing in infants presenting in the newborn period with diazoxide-responsive hyperinsulinemic hypoglycemia, even in the absence of maternal diabetes and macrosomia. The paternal grandparents were negative for this mutation, confirming a paternal de novo mutation and autosomal dominant inheritance in this family. Proband's elder sister, born at term appropriate for gestational age, presented with transient neonatal hypoglycemia needing parenteral glucose infusion for a week followed by spontaneous resolution. Father was diagnosed with Type 1 diabetes at 15 years of age that required insulin therapy. Cascade genetic screening identified the same mutation in his father and elder sister, but mother was negative. Glucose regulation was optimized using diazoxide upon confirmation of hyperinsulinism. He was born to a non-obese and non-diabetic mother. The proband was a term, appropriate-for-gestational age male infant with symptomatic hypoglycemia on day 3 of life needing high glucose infusion rate to maintain normoglycemia. We report a family with a novel HNF4A mutation with diverse phenotypic presentations of glucose dysregulation. Of the MODY genes described to date, only hepatocyte nuclear factor-4-alpha ( HNF4A MODY1) and hepatocyte nuclear factor-1-alpha (HNF1A MODY3) mutations may result in a biphasic phenotype of hypoglycemia in early life and hyperglycemia in later life. In contrast, mutations in certain MODY genes can also present with transient or persistent hyperinsulinemic hypoglycemia in newborn infants, reflecting instead β-cell dysregulation. Maturity-onset diabetes of the young (MODY) classically describes dominantly inherited forms of monogenic diabetes diagnosed before 25 years of age due to pancreatic β-cell dysfunction.
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