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Hyperinsulinism due to HNF4A deficiency
Hyperinsulinism due to HNF4A deficiency is a form of diazoxide-sensitive diffuse hyperinsulinism (DHI), characterized by macrosomia, transient or persistent hyperinsulinemic hypoglycemia (HH), responsiveness to diazoxide and a propensity to develop maturity-onset diabetes of the young subtype 1 (MODY-1; see this term).
ORPHA:263455Classification level: Disorder
- Hyperinsulinemic hypoglycemia due to HNF4A deficiency
- Prevalence: Unknown
- Inheritance: Autosomal dominant
- Age of onset: Infancy, Neonatal
- ICD-10: E16.1
- OMIM: -
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Hyperinsulinism due to HNF4A mutations are presumably the third most common genetic cause of DHI.
The disease frequently presents as neonatal hypoglycemia. The manifestations range from mild transient hypoglycemia, limited to the neonatal period to severe and persistent HH. Macrosomia is common, with mutation carriers having an increased birth weight by a median of 790 grams. Patients are at increased risk of developing MODY syndrome in later life. All patients are responsive to medical management with diazoxide. Family history of diabetes is usually, but not always present.
Hyperinsulinism due to HNF4A deficiency is caused by mutations in HNF4Agene (20q13.12), but the mechanism of HH is not understood. The HNF4A gene encodes for HNF-4alpha (hepatocyte nuclear factor 4-alpha), a transcription factor that has a key role in regulating the multiple transcriptional factor networks in the islet and, in combination with other hepatocyte nuclear factors (such as HNF-1alpha) form a functional regulatory loop in the adult pancreatic beta-cell. HNF-4-alpha binds to the promoters of 11% of islet genes. Thus HNF-4alpha deficiency probably exhibits its phenotype via abnormal expression of one or more of these target islet genes. HNF4A mutations have also been known to cause MODY syndrome.
The transmission is autosomal dominant with variable penetrance. De novo mutations have also been reported.
- Review article
- English (2011)