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Hepatocyte nuclear factor 4 alpha and its role in hyperinsulinaemic hypoglycaemia
*Corresponding author: V. Nancy Jeniffer, Department of Pediatrics, M. S. Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India. nancyphysician@gmail.com
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Received: ,
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How to cite this article: Somashekar AR, Sindhu K, Ruchitha R, Jeniffer VN. Hepatocyte nuclear factor 4 alpha and its role in hyperinsulinaemic hypoglycaemia. Karnataka Paediatr J. 2025;40:251-3 doi: 10.25259/KPJ_17_2025
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4A) mutations are the third most common genetic cause of hyperinsulinaemic hypoglycaemia after KCNJ11 and ABCC8 mutations. Transient or chronic neonatal hypoglycaemia results from inactivating HNF4A mutations, which affect insulin control in pancreatic β-cells. Mutations in the inactivating HNF4A gene impact insulin regulation in the pancreatic β-cells, causing either temporary or persistent hypoglycaemia in newborns. Less than 20 pathogenic variations of heterozygous mutations in the transcription factor HNF4A have been identified to date, making them a rare cause of maturity-onset diabetes of the young (MODY). We describe a 19-month-old boy who needs a glucose infusion to maintain normoglycaemia due to persistent hyperinsulinaemic hypoglycaemia. He was prescribed diazoxide, which was titrated to 2.5 mg/kg/ day, after he began experiencing frequent hypoglycaemic seizures. This medication successfully stabilised his blood glucose levels. A heterozygous HNF4A mutation was found by genetic testing (c.148T>C; p.Tyr 50His, exon 2). After starting diazoxide, there were no more hypoglycaemic episodes or seizures. The significance of taking into account HNF4A mutations in patients who need diazoxide due to persistent hypoglycaemia, even in the absence of macrosomia or a family history of diabetes, is demonstrated by this case. Given that some HNF4A carriers develop MODY later in life, early genetic diagnosis can direct long-term metabolic surveillance.
Keywords
Fanconi renotubular syndrome 4
Hepatocyte nuclear factor 4-α
Hyperinsulinaemia
Hypoglycaemic seizures
Maturity-onset diabetes in the young
INTRODUCTION
A member of the steroid/thyroid hormone receptor superfamily, hepatocyte nuclear factor 4 alpha (HNF4A), is primarily expressed in the kidney, liver, pancreatic islets and intestine. It is a key activator of HNF1A, which controls many genes specific to the liver that are involved in the metabolism of fatty acids, glucose and cholesterol.[1,2]
The main cause of maturity-onset diabetes of the young (MODY) is heterozygous mutations in HNF4A. Mutations in HNF4A account for 2 - 5 % of all cases of MODY.[3] At least 18 cases, including eight unrelated probands, have been reported to have one particular pathogenic variant, c.253C>T (p.Arg85Trp). This leads to a more general syndrome called Fanconi renotubular syndrome 4 with MODY, which presents as liver involvement, macrosomia, tubular nephropathy with hypophosphatemic rickets and hyperinsulinism that progresses to MODY.
Infants and children are susceptible to hyperinsulinaemic hypoglycaemia (HH), a rare condition that occurs in 1 in 50,000–1 in 2,500 births. Heterozygous inactivating mutations in HNF4A have been demonstrated to cause MODY1, which usually manifests in adolescence or adulthood.[4]
Maturity-onset diabetes
MODY is caused by impaired insulin secretion due to faulty pancreatic islet cell development. Its penetrance and expressivity vary, and its inheritance pattern is autosomal dominant among affected individuals. MODY accounts for <5% of all diabetes cases. About 6.5% of children with antibody-negative diabetes may have MODY. MODY is frequently misdiagnosed because its clinical characteristics overlap with those of Type 1 and Type 2 diabetes. Adaptor protein phosphotyrosine interacting with ph domain and leucine zipper 1 (APPL1), glucokinase (GCK), HNF1A, HNF4A, HNF1B, insulin (INS), neurogenic differentiation 1 (NEUROD1), pancreatic and duodenal homeobox 1 (PDX1), paired box genes (PAX), ATP binding cassette subfamily C member 8 (ABCC8), potassium inwardly-rectifying channel subfamily J member 11 (KCNJ11), krüppel-like factor 11 (KLF11), carboxyl ester lipase (CEL), B-lymphoid tyrosine kinase (BLK) are among the at least 14 distinct gene mutations linked to MODY [Table 1].[7]
| Study and mutation | Age of onset | Symptoms | Treatment | Prognosis |
|---|---|---|---|---|
| Chandran et al.[5] (2022) p.Asp345Tyr (c. 1033G >T) |
1 week | Neonatal hyperbilirubinemia, cyanosis | Diazoxide | Controlled till 36 months |
| Arya et al.[1] (2014) p.M116I (c. 317G >A) | 5 years | Macrosomia, neonatal HH | Diazoxide | Resolved by 18 months |
| Arslan et al.[6] (2020) c. 266G >A (p.R89Q) | 8 months | Vomiting, seizures | Diazoxide | Controlled till 14 months |
HNF4A: Hepatocyte nuclear factor 4 alpha, HH: Hyperinsulinaemic hypoglycaemia
CASE REPORT
We present a 19-month-old boy with HH due to an HNF4A mutation, requiring diazoxide therapy.
Clinical presentation
A previously healthy 19-month-old male presented with cold and cough for 4 days, fever for 1 day, and an episode of upward eye deviation lasting 20–30 s. A prior history at 14 months included three episodes of tonic-clonic seizures with glucose levels as low as 27 mg/dL, requiring dextrose boluses.
The initial assessment revealed stable vitals and unremarkable systemic examination. Magnetic resonance imaging of the brain was normal. The metabolic work was as follows:
Hypoglycaemia in spite of dextrose boluses (General random blood sugar [GRBS]: 37 mg/dL)
High levels of insulin (0.969 µIU/mL) and C-peptide (0.89 ng/mL), which are indicative of hyperinsulinaemia
Normal levels of growth hormone (3.27 ng/mL) and cortisol (17.6 µg/dL)
Ketonuria and metabolic acidosis in venous blood gas.
Management included hypoglycaemia correction with IV 10% dextrose bolus (10 mL/kg) and increased glucose infusion rate (6.6 mg/kg/min)
Diazoxide therapy was initiated following an endocrinology consultation. A diet based on cornflour was introduced.
Seizures were managed with IV levetiracetam, and breakthrough events with IV midazolam.
Hospital course
The child was admitted to PICU for close monitoring with gradual tapering of intravenous fluids (IVF), discharged on oral feeds and diazoxide. In view of the suspicion of the genetic cause of HH, whole exome sequencing (WES) identified a heterozygous missense variant in the HNF4A gene, c.148T>C (p.Tyr50His), exon 2.
Parental genetic evaluation was done; no abnormalities were detected.
DISCUSSION
The diagnostic complexity of MODY linked to Fanconi’s renotubular syndrome is highlighted by this case, especially when recurrent seizures and persistent hypoglycaemia are present.
HNF4A mutations result in a broad phenotypic spectrum, from mild dietary-responsive hypoglycaemia to severe diazoxide-dependent HH. Although the precise mechanism is still unknown, HNF4A interacts with Peroxisome proliferator-activated receptor alpha (PPAα), which is essential for fatty acid β-oxidation, and controls transcription factors in pancreatic β-cells.[6]
Mechanism of action of diazoxide
Diazoxide raises glucose levels by inhibiting insulin secretion. It binds to the pancreatic adenosine triphosphate (ATP) sensitive potassium channel (KATP) channels’ sulfonylurea receptor 1 subunit, increasing potassium ion permeability and causing β-cell hyperpolarisation, which stops insulin from being released.[6] The mutation identified in our case, c.148T>C (p.Tyr50His), is located in exon 2 of the HNF4A gene. Furthermore, HH has been linked to a number of mutations outside of this region. Further research is needed to understand better the relationship between HNF4A mutations and HH, and their broader implications in metabolic regulation [Figure 1].[8]
- Mechanism of action of diazoxide. K ATP: K dependent adenosine tTriphosphate, ATP: Adenosine triphosphate, SUR 1: Sulfonylurea receptor 1
CONCLUSION
This case emphasises the importance of early detection, genetic testing and suitable treatment for HH associated with HNF4A. Given its association with MODY and Fanconi renotubular syndrome, long-term follow-up is crucial to monitor metabolic transitions and optimising management strategies.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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