Hyperinsulinemic Hypoglycemia in Three Generations of a Family with Glucokinase Activating Mutation, c.295T>C (p.Trp99Arg).

Aleksandra Gilis-Januszewska,Alicja Hubalewska-Dydejczyk,Elwira Przybylik-Mazurek,Karolina Soczówka,Artur Kowalik,Ewelina Rzepka,Bogusław Głowa,Anna Bogusławska

doi:10.3390/genes12101566

Aleksandra Gilis-Januszewska, Alicja Hubalewska-Dydejczyk + Show 6 more

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https://doi.org/10.3390/genes12101566

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Abstract

Familial Hyperinsulinemic Hypoglycemia (FHH) is a very rare disease with heterogeneous clinical manifestations. There are only a few reports of heterozygous activating mutations of glucokinase (GCK) attributable to FHH, with no reports describing effects in the course in pregnancy with affected mother/affected child. A large kindred with FHH and GCK:c.295T>C (p.Trp99Arg) pathogenic variant was identified in which four family members from three generations were affected. The clinical follow up in one clinical center lasted up to 30 years, with different times of diagnosis ranging from neonate period to adulthood. The severity of hypoglycemia was mild/severe and fasting was the trigger for hypoglycemia. Response to diazoxide varied from good, in the neonate, to moderate/poor, in childhood/adulthood; however, this was biased by poor compliance. Treatment with somatostatin analogues was discontinued due to side effects. Over time, patients developed clinical adaptation to very low glucose levels. During pregnancy, episodes of severe hypoglycemia in the first trimester were observed, which responded very well to steroids. The clinical course of the GCK:c.295T>C (p.Trp99Arg) mutation varied in the same family, with the development of clinical adaptation to very low glucose levels over time. Treatment with steroids might prevent hypoglycemia during pregnancy in an affected mother.

Highlights

Familial Hyperinsulinemic Hypoglycemia (FHH) is a very rare disease characterized by excessive insulin secretion from pancreatic β-cells independent of glucose serum level
Familial Hyperinsulinemic Hypoglycemia has been correlated with pathogenic variants in 15 genes: ABCC8, KCNJ11, GCK, GLUD-1, HADH1, SLC16A1, HNF4A, HNF1A, UCP2, PMM2, CACNA1D, HK1, PGM1, FOXA2 and EIF2S3
22 different GCK pathogenic variants have been reported, and these reports of hyperinsulinism related to the GCK mutation might vary from a mil hypoglycemia, which can be managed with diazoxide as reported in most severe clinical phenotype of uncontrollable hypoglycemia leading to d

Summary

Introduction

Familial Hyperinsulinemic Hypoglycemia (FHH) is a very rare disease characterized by excessive insulin secretion from pancreatic β-cells independent of glucose serum level. Familial Hyperinsulinemic Hypoglycemia has been correlated with pathogenic variants in 15 genes: ABCC8, KCNJ11, GCK, GLUD-1, HADH1, SLC16A1, HNF4A, HNF1A, UCP2, PMM2, CACNA1D, HK1, PGM1, FOXA2 and EIF2S3. These mutations have been associated with approximately 48% of cases [1]. 22 different GCK pathogenic variants have been reported, and these reports of hyperinsulinism related to the GCK mutation might vary from a mil hypoglycemia, which can be managed with diazoxide as reported in most severe clinical phenotype of uncontrollable hypoglycemia leading to d

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Conclusion