title: Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.
abstract: BACKGROUND
  Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.
  
  
  RESULTS
  We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth.
  
  
  CONCLUSIONS
  HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.
authors.affiliation: Peninsula Medical School, Exeter, United Kingdom.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Boj
authors.forename: Anna M
authors.initials: AM
authors.lastname: Steele
authors.forename: Timothy
authors.initials: T
authors.lastname: Barrett
authors.forename: Karen
authors.initials: K
authors.lastname: Stals
authors.forename: Julian P
authors.initials: JP
authors.lastname: Shield
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001724:Birth Weight; D001786:Blood Glucose / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005320:Fetal Macrosomia / Q000235:genetics* / Q000503:physiopathology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital / Q000235:genetics; D007003:Hypoglycemia / Q000151:congenital / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D011247:Pregnancy; D015995:Prevalence; D012189:Retrospective Studies
chemical_list: D001786:Blood Glucose; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin