ArticlePLoS medicine2007
Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.
Article in PLoS medicine, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 178 papers, 2 of them syntheses that pooled it.
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178 citing papers in PubMed, 2 syntheses or guidelines pooled it, 417 citations in OpenAlex.
- International Guidelines for the Diagnosis and Management of Hyperinsulinism.Hormone research in paediatrics · 2024Guideline
- Variable phenotypes of individual and family monogenic cases with hyperinsulinism and diabetes: a systematic review.Reviews in endocrine & metabolic disorders · 2022Pooled it
- Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial.Genetics in medicine : official journal of the American College of Medical Genetics · 2018 · on this mapTrial
- Dual phenotype in a patient with adult-onset hyperinsulinism and diabetes caused by an activatingJournal of the Endocrine Society · 2026Article
- Phenotypic Spectrum of HNF4α-Associated Fanconi Renotubular Syndrome.Kidney international reports · 2026Article
- Hyperinsulinaemia as a cause of obesity and cardiometabolic diseases.Nature reviews. Endocrinology · 2026Review
- Maturity onset diabetes of the young in pregnancy: management, treatment and neonatal outcomes-a systematic review.Acta diabetologica · 2026Review
- Insights from maturity-onset diabetes of the young into impaired insulin secretion in type 2 diabetes.Endocrine journal · 2026Review
- Antenatal management ofJCEM case reports · 2026Article
- The interplay of maturity-onset diabetes of the young, obesity, uncontrolled hypertension, and cannabinoid hyperemesis in the progression to end-stage renal disease: a case report.Frontiers in medicine · 2026Article
- Sulphonylurea efficacy and end-organ outcomes in the management of HNF4A-MODY.Diabetic medicine : a journal of the British Diabetic Association · 2025Article
- Genetic and clinical characteristics of children with mody: insights into novel HNF4A variants and genotype-phenotype correlation.Irish journal of medical science · 2025Article
- Neonatal hypoglycaemia in the offsprings of parents with maturity-onset diabetes of the young (MODY).Journal of pediatric endocrinology & metabolism : JPEM · 2025Review
- Hidden MODY in Young Lean Women with Mild Glucose Intolerance Detected during Health Check-ups: Potential for Improved Pregnancy Outcomes through Preconception Care.Internal medicine (Tokyo, Japan) · 2025Article
- Unraveling the genetic basis of MODY: insights from next-generation sequencing.Journal of applied genetics · 2025Article
- Decoding MODY: exploring genetic roots and clinical pathways.Diabetology international · 2025Review
- Congenital Hyperinsulinism India Association: An Approach to Address the Challenges and Opportunities of a Rare Disease.Medical sciences (Basel, Switzerland) · 2025Review
- Diabetes mellitusFrontiers in endocrinology · 2025Article
- Revealing Monogenic Diabetes: Clinical and Genetic Features of Pediatric MODY Cases in Türkiye: Single Center Experience.Pediatric diabetes · 2025Article
- Actionability of Genetic Variants in Diabetes: Core Aspects and Applied Examples.Diabetes spectrum : a publication of the American Diabetes Association · 2025Article
118 more citing papers are in PubMed but not listed here.
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9 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundMacrosomia 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. METHODS AND
findingsWe 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.
conclusionsHNF4A 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.
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