Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Abstract

What is already known on this topic?Homozygous ABCC8 mutations cause severe persistent diffuse hyperinsulinemic hypoglycaemia (HH) which is usually diazoxide unresponsive and requires surgical therapy. In medically managed patients with congenital hyperinsulinism (CHI), disease symptoms become milder overtime. Hyperinsulinemic hypoglycemia at neonatal period and later diabetes have been reported in heterozygous mutation of HNF4A and HNF1A as well as heterozygous ABCC8 mutations What this study adds? We describe the first homozygous ABCC8 mutation with HH at neonatal period and evolution to complete insulin deficient, sulphonylurea responsive diabetes mellitus. Findings from present work which show a broad range of clinical spectrum from asymptomatic, mild symptomatic hypoglycemia, severe hypoglycemia as well as insulin deficient diabetes mellitus in family members with identical mutation confirms the phenotypical variations in ABCC8 mutations Present case report emphasizes the need for long-term follow up of patients with HH at neonatal period due to ABCC8 mutations, particularly those managed with medical therapy for risk of developing diabetes in later life. Abstract:Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. Recessive inactivating mutations in the ABCC8 and KCNJ11 genes account for approximately 50 % of all CHI cases. Hyperinsulinaemic hypoglycaemia (HH) in infancy and diabetes in later life have been reported in subjects with HNF1A, HNF4A and ABCC8 mutations. Case report: Herein, we present a child who was diagnosed with CHI at birth, then developed diabetes mellitus at the age of 9 years due to a novel homozygous missense, p.L171F (c.511C>T) mutation in the exon 4 of ABCC8. The parents and one sibling were heterozygous carriers, whilst a younger sibling who had transient neonatal hypoglycemia was homozygous for the mutation. The mother and (maternal) uncle, who was also heterozygous for the mutation, developed diabetes within their third decade of life. The preliminary results of sulphonylurea (SU) treatment was suggestive for SU responsiveness. Patients with homozygous ABCC8 mutations can present with CHI in the newborn period, the hyperinsulinism can show variability in terms of clinical severity and age at presentation and can cause diabetes later in life. Patients with homozygous ABCC8 mutations who are managed medically should be followed as they may be at increased risk of developing diabetes.

The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism

“…Huopio et al (45) have reported a development of impaired glucose tolerance in 75% of the mothers during pregnancy while Pinney et al (42) have not seen such a positive trend toward diabetes in mutation carriers. More recently, we reported a family carrying a novel missense c.511C>T (p.L171F) variant in exon 4 of ABCC8 which lead to adult onset diabetes in heterozygous carriers, while a homozygous carrier developed HH at neonatal period and diabetes later in life (47).…”

Congenital hyperinsulinism—A case of mild hypoglycemia in an adult, detected by family testing

“…Subtle symptoms of hyperinsulinaemic hypoglycemia followed by diabetes later in life, have been reported in patients with dominant mutations in ABCC8 genes in a limited number of cases 3 …”

“…The underlying mechanism in cases with dominant ABCC8 mutations, which develop hyperglycemia later in life, is unclear. Possible explanations include dysregulated insulin secretion by progressive failure in beta cell function due to ‘exhaustion’, beta cell apoptosis caused by raised intracellular calcium concentration, or the influence of other genetic or environmental factors 3,4 …”

“…Subtle symptoms of hyperinsulinaemic hypoglycemia followed by diabetes later in life, have been reported in patients with dominant mutations in ABCC8 genes in a limited number of cases. 3 The underlying mechanism in cases with dominant ABCC8 mutations, which develop hyperglycemia later in life, is unclear. Possible explanations include dysregulated insulin secretion by progressive failure in beta cell function due to 'exhaustion', beta cell apoptosis caused by raised intracellular calcium concentration, or the influence of other genetic or environmental factors.…”

Targeted gene panel analysis of Japanese patients with maturity‐onset diabetes of the young‐like diabetes mellitus: Roles of inactivating variants in the ABCC8 and insulin resistance genes

“…Cases of K ATP channel congenital hyperinsulinism evolving into diabetes have been reported repeatedly 43–46 . This is likely to be a different category of K ATP channel MODY distinct from the patients with activating variants.…”