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Hyperinsulinism due to HNF4A deficiency

MedGen UID:
894506
•Concept ID:
C4274078
•
Disease or Syndrome
Synonym: Congenital hyperinsulinism due to HNF4A deficiency
SNOMED CT: Hyperinsulinism due to hepatocyte nuclear factor 4-alpha deficiency (717048002); Hyperinsulinism due to HNF4A deficiency (717048002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Monarch Initiative: MONDO:0016988
Orphanet: ORPHA263455

Definition

A form of diazoxide-sensitive diffuse hyperinsulinism characterised by macrosomia, transient or persistent hyperinsulinaemic hypoglycaemia, responsiveness to diazoxide and a propensity to develop maturity-onset diabetes of the young subtype 1. The disease frequently presents as neonatal hypoglycaemia. All patients are responsive to medical management with diazoxide. Family history of diabetes is usually, but not always present. Caused by mutations in HNF4A gene (20q13.12). The transmission is autosomal dominant with variable penetrance. [from SNOMEDCT_US]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • Hyperinsulinism due to HNF4A deficiency

Recent clinical studies

Etiology

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.
Xiao X, Li R, Cui B, Lv C, Zhang Y, Zheng J, Hui R, Wang Y
EMBO J 2024 Feb;43(4):507-532. Epub 2024 Jan 8 doi: 10.1038/s44318-023-00020-1. PMID: 38191811Free PMC Article
Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes.
Bonnefond A, Semple RK
Diabetologia 2022 Nov;65(11):1782-1795. Epub 2022 May 27 doi: 10.1007/s00125-022-05720-7. PMID: 35618782Free PMC Article
Vitamin D receptor targets hepatocyte nuclear factor 4α and mediates protective effects of vitamin D in nonalcoholic fatty liver disease.
Zhang H, Shen Z, Lin Y, Zhang J, Zhang Y, Liu P, Zeng H, Yu M, Chen X, Ning L, Mao X, Cen L, Yu C, Xu C
J Biol Chem 2020 Mar 20;295(12):3891-3905. Epub 2020 Feb 12 doi: 10.1074/jbc.RA119.011487. PMID: 32051143Free PMC Article
Hepatocyte Nuclear Factor-4α P2 Promoter Variants Are Associated With the Risk of Metabolic Syndrome and Testosterone Deficiency in Aging Taiwanese Men.
Liu CC, Lee YC, Huang SP, Cheng KH, Hsieh TJ, Huang TY, Lee CH, Geng JH, Li CC, Wu WJ
J Sex Med 2018 Nov;15(11):1527-1536. doi: 10.1016/j.jsxm.2018.09.012. PMID: 30415809
Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT
PLoS Med 2007 Apr;4(4):e118. doi: 10.1371/journal.pmed.0040118. PMID: 17407387Free PMC Article

Diagnosis

Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A.
Stanescu DE, Hughes N, Kaplan B, Stanley CA, De León DD
J Clin Endocrinol Metab 2012 Oct;97(10):E2026-30. Epub 2012 Jul 16 doi: 10.1210/jc.2012-1356. PMID: 22802087Free PMC Article
Glucose-dependent regulation of NR2F2 promoter and influence of SNP-rs3743462 on whole body insulin sensitivity.
Boutant M, Ramos OH, Lecoeur C, Vaillant E, Philippe J, Zhang P, Perilhou A, Valcarcel B, Sebert S, Jarvelin MR, Balkau B, Scott D, Froguel P, Vaxillaire M, Vasseur-Cognet M
PLoS One 2012;7(5):e35810. Epub 2012 May 14 doi: 10.1371/journal.pone.0035810. PMID: 22606236Free PMC Article

Therapy

Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes.
Bonnefond A, Semple RK
Diabetologia 2022 Nov;65(11):1782-1795. Epub 2022 May 27 doi: 10.1007/s00125-022-05720-7. PMID: 35618782Free PMC Article
Vitamin D receptor targets hepatocyte nuclear factor 4α and mediates protective effects of vitamin D in nonalcoholic fatty liver disease.
Zhang H, Shen Z, Lin Y, Zhang J, Zhang Y, Liu P, Zeng H, Yu M, Chen X, Ning L, Mao X, Cen L, Yu C, Xu C
J Biol Chem 2020 Mar 20;295(12):3891-3905. Epub 2020 Feb 12 doi: 10.1074/jbc.RA119.011487. PMID: 32051143Free PMC Article
Cholesterol sulfate and cholesterol sulfotransferase inhibit gluconeogenesis by targeting hepatocyte nuclear factor 4α.
Shi X, Cheng Q, Xu L, Yan J, Jiang M, He J, Xu M, Stefanovic-Racic M, Sipula I, O'Doherty RM, Ren S, Xie W
Mol Cell Biol 2014 Feb;34(3):485-97. Epub 2013 Nov 25 doi: 10.1128/MCB.01094-13. PMID: 24277929Free PMC Article

Prognosis

Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes.
Bonnefond A, Semple RK
Diabetologia 2022 Nov;65(11):1782-1795. Epub 2022 May 27 doi: 10.1007/s00125-022-05720-7. PMID: 35618782Free PMC Article
Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT
PLoS Med 2007 Apr;4(4):e118. doi: 10.1371/journal.pmed.0040118. PMID: 17407387Free PMC Article

Clinical prediction guides

Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT
PLoS Med 2007 Apr;4(4):e118. doi: 10.1371/journal.pmed.0040118. PMID: 17407387Free PMC Article

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