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Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the HNF4A gene.

ABSTRACT: SUMMARY:HNF4A gene mutations have been reported in cases of transient and persistent hyperinsulinaemic hypoglycaemia of infancy (HHI), particularly in families with adulthood diabetes. The case of a patient with HHI, liver impairment and renal tubulopathy due to a mutation in HNF4A is reported. LEARNING POINTS:Urine specimen study in cases of HHI with diazoxide response is necessary to rule out specific metabolic conditions (l-3-hydroxyacyl-coenzyme A dehydrogenase deficiency) or tubular renal involvement.Hyperinsulinaemic hypoglycaemia due to the heterozygous mutation (p.Arg63Trp, c. 187C?>?T) in the HNF4A gene is associated with renal tubulopathy and liver involvement.Follow-up of patients diagnosed of HHI is mandatory to detect associated conditions.

SUBMITTER: Clemente M

PROVIDER: S-EPMC5404475 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the <i>HNF4A</i> gene.

Clemente María M Vargas Alejandro A Ariceta Gema G Martínez Rosa R Campos Ariadna A Yeste Diego D

Endocrinology, diabetes & metabolism case reports 20170316

<h4>Summary</h4><i>HNF4A</i> gene mutations have been reported in cases of transient and persistent hyperinsulinaemic hypoglycaemia of infancy (HHI), particularly in families with adulthood diabetes. The case of a patient with HHI, liver impairment and renal tubulopathy due to a mutation in <i>HNF4A</i> is reported.<h4>Learning points</h4>Urine specimen study in cases of HHI with diazoxide response is necessary to rule out specific metabolic conditions (l-3-hydroxyacyl-coenzyme A dehydrogenase d ...[more]

PMID: 28458902

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Project description: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-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 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 beta-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.

Dataset Information

Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the HNF4A gene.

Publications

Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the <i>HNF4A</i> gene.

Similar Datasets

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