Monogenic Neonatal Diabetes Mellitus

Monogenic neonatal diabetes mellitus is persistent hyperglycaemia presenting before 6 months of age because of a single gene defect. It is permanent or transient, and some forms respond to oral sulphonylurea instead of insulin.

It is rare, of the order of 1 in 100,000 live births. Type 1 diabetes is very rare under 6 months, so any infant with diabetes in this age range should have genetic testing.

Permanent causes are KCNJ11 and ABCC8 (ATP-sensitive potassium channel, most common), INS (dominant misfolding), GCK (biallelic), PDX1, PTF1A, GATA6, EIF2AK3 (Wolcott-Rallison type), FOXP3 (enteropathy and autoimmunity). Transient causes are overexpression at 6q24 (imprinting), and some KCNJ11, ABCC8 and INS variants.

Transient forms remit in the first months and may relapse around puberty or adulthood.

Pathophysiology.

Activating variants in the potassium channel keep the channel open, blocking insulin release. Insulin gene variants cause misfolded proinsulin and beta cell stress.

Insulin acts as a foetal growth factor, so affected infants are small for gestational age. Pancreatic agenesis syndromes also cause exocrine failure.

• Growth restriction, low birth weight, then hyperglycaemia, dehydration, polyuria, weight loss and poor feeding from the first days to weeks. Ketoacidosis is frequent.
• Severe potassium channel variants cause neurological features (developmental delay, epilepsy, muscle hypotonia).
• Extra-pancreatic clues: epiphyseal dysplasia and liver failure (EIF2AK3), cerebellar hypoplasia and exocrine failure (PTF1A), congenital heart disease (GATA6), enteropathy and eczema (FOXP3).

Red flags.

• Ketoacidosis, seizures or hypoglycaemia in an infant, and glucose over 14 mmol/L with dehydration.

• Glucose 7.0 mmol/L or more on two samples (with ketones if acute) in an infant under 6 months, excluding hyperglycaemia from sepsis, prematurity or glucose infusion.
• Islet autoantibodies (usually negative) and C-peptide.
• Urgent molecular genetic testing of a neonatal diabetes panel: results in days to weeks and can change treatment. Include 6q24 methylation analysis.
• Stool elastase, liver tests, echocardiogram, brain imaging and other tests directed by the clinical features.

Differential diagnosis.

• Stress hyperglycaemia of illness, drugs (steroids) or intravenous dextrose in premature infants.
• Type 1 diabetes (autoantibody positive, rare under 6 months).
• Maternal diabetes related transient hyperglycaemia and other syndromic causes (Wolfram syndrome and congenital pancreatic hypoplasia).

• Acute ketoacidosis: intravenous fluids over 48 hours with careful correction, insulin 0.05 to 0.1 units/kg/h, potassium replacement and frequent glucose checks. Cerebral oedema is a recognised risk in children, so correct fluid and glucose deficits gradually.
• Start subcutaneous insulin (dilute or by pump) while awaiting genetics.
• KCNJ11 or ABCC8 variants: transition to glibenclamide. Start 0.1 mg/kg daily in two divided doses, increase by 0.1 to 0.2 mg/kg daily every 2 to 3 days while reducing insulin, usual final dose 0.2 to 0.5 mg/kg daily (up to 1 mg/kg daily occasionally; higher only under specialist supervision). Stop insulin when glucose is stable. Transfer is done in hospital with frequent glucose checks.
• Other forms: insulin, pancreatic enzymes (PTF1A, pancreatic agenesis), and organ specific care.
• Transient forms: insulin until remission, then monitoring.

Genetic counselling. Autosomal dominant forms carry a 50% risk to offspring, recessive forms 25%, and some are de novo. Offer preconception counselling and pregnancy planning from adolescence.

Monitoring. Glucose daily, HbA1c every 3 months, growth and development, and drug review for sulphonylurea dose creep. Transient forms: lifelong screening, particularly at puberty and pregnancy.

Referral and escalation. Paediatric endocrinology and clinical genetics at diagnosis. Neurology for developmental delay or seizures.