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Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2.

ABSTRACT: Context:Persistent hypoglycemia in the newborn period most commonly occurs as a result of hyperinsulinism. The phenotype of hypoketotic hypoglycemia can also result from pituitary hormone deficiencies, including growth hormone and adrenocorticotropic hormone deficiency. Forkhead box A2 (Foxa2) is a transcription factor shown in mouse models to influence insulin secretion by pancreatic ? cells. In addition, Foxa2 is involved in regulation of pituitary development, and deletions of FOXA2 have been linked to panhypopituitarism. Objective:To describe an infant with congenital hyperinsulinism and hypopituitarism as a result of a mutation in FOXA2 and to determine the functional impact of the identified mutation. Main Outcome Measure:Difference in wild-type (WT) vs mutant Foxa2 transactivation of target genes that are critical for ? cell function (ABCC8, KNCJ11, HADH) and pituitary development (GLI2, NKX2-2, SHH). Results:Transactivation by mutant Foxa2 of all genes studied was substantially decreased compared with WT. Conclusions:We report a mutation in FOXA2 leading to congenital hyperinsulinism and hypopituitarism and provide functional evidence of the molecular mechanism responsible for this phenotype.

SUBMITTER: Vajravelu ME

PROVIDER: S-EPMC6276717 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2.

Vajravelu Mary Ellen ME Chai Jinghua J Krock Bryan B Baker Samuel S Langdon David D Alter Craig C De León Diva D DD

The Journal of clinical endocrinology and metabolism 20180301 3

<h4>Context</h4>Persistent hypoglycemia in the newborn period most commonly occurs as a result of hyperinsulinism. The phenotype of hypoketotic hypoglycemia can also result from pituitary hormone deficiencies, including growth hormone and adrenocorticotropic hormone deficiency. Forkhead box A2 (Foxa2) is a transcription factor shown in mouse models to influence insulin secretion by pancreatic β cells. In addition, Foxa2 is involved in regulation of pituitary development, and deletions of FOXA2 h ...[more]

PMID: 29329447

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Project description:IntroductionCongenital hyperinsulinism is a rare inherited disease caused by mutations in genes responsible for β-cell's function in glucose hemostasis leading to profound and recurrent hypoglycemia. The incidence of the disease is about 1 in 50000 newborns. Mutations in at least 8 genes have been reported to cause congenital hyperinsulinism. Mutations in ABCC8 gene are the most common cause of the disease that account for approximately 40% of cases. Less frequently KCNJ11 gene mutations are responsible for the disease. Mutations in other genes such as HADH account for smaller fractions of cases. In nearly half of the cases the cause remains unknown.Case presentationDuring the period between 2005 and 2010, a total of six patients with persistent hyperinsulinism were investigated at Mofid Children's Hospital. In this study all of the patients had early onset hyperinsulinemia. Five patients had consanguineous parents. After failure of medical treatment in three patients, They were undergone pancreatectomy. Two diffuse types and one focal type had been recognized in pathological analysis of intra-operative frozen specimens of pancreas in these patients. Genetic analysis was performed using polymerase chain reaction followed by Sanger sequencing for ABCC8, KCNJ11and HADH genes. In five patients homozygous mutations in these genes were identified that indicated an autosomal recessive pattern of inheritance. In one patient a heterozygous mutation in ABCC8 was identified, indicating possible autosomal dominant inheritance of the disease.ConclusionsCongenital hyperinsulinism can have different inheritance pattern. Autosomal recessive inheritance is more common but less frequently autosomal dominant inheritance can be seen. It appears that mutations in ABCC8 gene can show both autosomal recessive and autosomal dominant inheritance of the disease. PCR followed by Sanger sequencing proved to be an efficient method for mutation detection in three investigated genes. Despite early diagnosis, psychomotor retardation was seen in two patients.

Dataset Information

Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2.

Publications

Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2.

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