Introduction

Pancreatic beta-cell dysfunction in the newborn period can lead either tohypoglycaemia or hyperglycemia. Hypoglycaemia occurs due to inappropriateinsulin secretion which leads to hyperinsulinaemic hypoglycaemia (HH). Hyperglycemia occurs due to too little insulin secretion and this lead toneonatal diabetes mellitus (NDM). Genetic defects in nine different genes havebeen described which lead to HH. On the other NDM can be due to defects in alarge number of genes.

Hyperinsulinaemic hypoglycaemia

Insulin secretion from pancreatic β-cells is tightly regulated to keep fastingblood glucose concentrations within the normal range (3.5–5.5mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is a heterozygous condition in whichinsulin secretion becomes unregulated and its production persists despite lowblood glucose levels. It is the most common cause of severe and persistenthypoglycaemia in neonates and children. The most severe and permanent forms are due to congenital hyperinsulinism (CHI). Recent advances in genetics have linked CHI to mutations in 9 genes that play a key role in regulating insulinsecretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A andHNF1A). Mutations in genes ABCC8 (SUR1 subunit) and KCNJ11 (Kir6.2 subunit)are the most common cause of CHI. Both the ABCC8/KCNJ11 genes arelocalized on chromosome 11p15.1. The most severe forms of CHI are due torecessive inactivating (loss of function) mutations in ABCC8 and KCNJ11 leading to unregulated insulin secretion despite severe hypoglycaemia. Dominant inactivating mutations in ABCC8 and KCNJ11 usually cause a milder form of CHI which is responsive to diazoxide. However, medically un-responsive forms have also been reported.

Histologically, CHI can be divided into 3 types: diffuse, focal and atypical. Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage. Therefore it is essential to diagnose and treat HH promptly. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children.

Neonatal diabetes mellitus

Neonatal diabetes mellitus is characterised by insulin-requiring hyperglycaemia within the first 6 months of life and has the opposite phenotype to CHI. The condition can either be permanent (PNDM), requiring lifelong insulin treatment or transient, where the condition can disappear during infancy but reappear inlater life (TNDM). Genetic disorders in a large number of greens have now been described which lead to either PNDM or TNDM. These gene defects can either be due to abnormalities in transcription factors which regulate pancreatic development, in key enzymes which control glucose metabolism in the betacellor in the genes (ABCC8/KCNJ11) which control the function of the pancreatic KATP channels.

Activating/gain of function mutations in KCNJ11 are the most common genetic cause of PNDM reported to date. Only dominantly-acting KCNJ11 mutations have been described in PNDM. The majority (80%) of these mutations have a risen de novo during embryogenesis and in a few cases mosaicism has been reported. A common KCNJ11 mutation (R201H) has also been found, whichleads to reduced sensitivity to ATP, preventing closure of KATP channels and reduced insulin secretion. ABCC8 mutations are less common in PNDM and are only found in 27% of patients in whom no KCNJ11 mutation has been found.These activating mutations are either heterozygous, homozygous or compound heterozygous for both activating and inactivating mutations. Although the majority of these mutations are sporadic (50%), mutations in ABCC8 can also bein herited recessively. A correct genetic diagnosis of NDM is very important as itcan affect treatment and clinical outcome. Patients with mutations in the ABCC8/KCNJ11 can be transferred onto oral therapy with sulphonylureas.