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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-4α) and  HNF1A/TCF1  (encoding HNF-1α), and the effect of pancreatic deletion of  Hnf4a  on foetal and neonatal insulin secretion in mice.    Methods and Findings  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 β-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.

Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A Gene