title: Congenital hyperinsulinism and glycogenosis-like phenotype due to a novel HNF4A mutation.
abstract: OBJECTIVE
  Congenital hyperinsulinism (CHI) and glycogen storage disease (glycogenosis) are both causing hypoglycemia during infancy, but with different additional clinical features and therapeutic approach. We aimed to identify a genetic cause in a child with an ambiguous phenotype.
  
  
  RESULTS
  We present a child with hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in erythrocytes, increased liver transaminases, and increased echogenicity on liver ultrasonography. As both parents of the proband were referred as healthy, we raised a clinical suspicion on glycogenosis with recessive inheritance. However, whole exome sequencing revealed no mutation in genes causing glycogenosis, but a novel heterozygous variant LRG_483t1: c.427-1G>A in the HNF4A gene was identified. Aberrant splicing resulting in in-frame deletion c.429_476del, p.(T144_I159del) was confirmed by sequencing of HNF4A transcripts reverse-transcribed from whole blood RNA. The same variant was found in five of eight tested family relatives (one of them already had diabetes, two had prediabetes). With regard to the results of DNA analysis, we added diazoxide to the therapy. Consequently, the frequency and severity of hypoglycemia in the proband decreased. We have also recommended sulfonylurea treatment after diabetes onset in adult mutation carriers.
  
  
  CONCLUSIONS
  We have identified a novel HNF4A gene mutation in our patient with CHI and glycogenosis-like phenotype. The proband and her family members benefited from the genetic testing by WES method and consequently personalized therapy. Nevertheless, the HNF4A gene testing may be considered in selected CHI cases with glycogenosis-like phenotype prior WES analysis.
authors.affiliation: First Department of Pediatrics, Medical Faculty of Comenius University and Children Faculty Hospital, Limbova 1, 833 40 Bratislava, Slovakia; DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center SAS, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Stanik
authors.affiliation: DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center SAS, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
authors.forename: Martina
authors.initials: M
authors.lastname: Skopkova
authors.affiliation: First Department of Pediatrics, Medical Faculty of Comenius University and Children Faculty Hospital, Limbova 1, 833 40 Bratislava, Slovakia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Brennerova
authors.affiliation: DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center SAS, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Danis
authors.affiliation: Department of Intensive Care in Neonatology, Medical Faculty of Comenius University and Children Faculty Hospital, Limbova 1, 833 40 Bratislava, Slovakia.
authors.forename: Monika
authors.initials: M
authors.lastname: Rosolankova
authors.affiliation: Department of Laboratory Medicine, Children Faculty Hospital, Limbova 1, 833 40 Bratislava, Slovakia.
authors.forename: Anna
authors.initials: A
authors.lastname: Salingova
authors.affiliation: First Department of Pediatrics, Medical Faculty of Comenius University and Children Faculty Hospital, Limbova 1, 833 40 Bratislava, Slovakia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bzduch
authors.affiliation: DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center SAS, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
authors.forename: Iwar
authors.initials: I
authors.lastname: Klimes
authors.affiliation: DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center SAS, Dubravska cesta 9, 845 05 Bratislava, Slovakia. Electronic address: daniela.gasperikova@savba.sk.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gasperikova
mesh_terms: D000328:Adult; D002648:Child; D044903:Congenital Hyperinsulinism / Q000235:genetics*; D005260:Female; D005838:Genotype; D006008:Glycogen Storage Disease / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype
chemical_list: D051557:Hepatocyte Nuclear Factor 4
keywords: Congenital hyperinsulinism; Glycogenosis – like phenotype; HNF4A; HNF4A-MODY; Hypoglycemia; Pharmacogenetics