Permanent Neonatal Diabetes Mellitus

Clinical characteristics: Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include intrauterine growth restriction, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. The course of PNDM varies by genotype.

Diagnosis/testing: Persistent hyperglycemia (plasma glucose concentration >150-200 mg/dL) in infants younger than age six months establishes the diagnosis of PNDM. Molecular testing is recommended: identification of pathogenic variant(s) in ABCC8 or KCNJ11 can guide treatment.

Management: Treatment of manifestations: Start rehydration and intravenous insulin infusion promptly after diagnosis. When the infant is stable and tolerating oral feedings begin subcutaneous insulin therapy. Children with pathogenic variants in ABCC8 or KCNJ11 can be treated with oral sulfonylureas; all others require long-term insulin therapy. High caloric intake is necessary for appropriate weight gain. Pancreatic enzyme replacement therapy is required for those with exocrine pancreatic insufficiency.

Prevention of secondary complications: Aggressive treatment and frequent monitoring of blood glucose concentrations to avoid acute complications such as diabetic ketoacidosis and hypoglycemia and reduce the long-term complications of diabetes mellitus.

Surveillance: Lifelong monitoring of blood glucose concentrations at least four times a day; periodic developmental evaluations. After age ten years, annual screening for chronic complications of diabetes mellitus including urinalysis for microalbuminuria and ophthalmologic examination for retinopathy.

Agents/circumstances to avoid: In general, avoid rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations (except as a continuous intravenous or subcutaneous infusion) as they may cause severe hypoglycemia in young children.

Genetic counseling: The mode of inheritance of PNDM is autosomal dominant for mutation of KCNJ11, autosomal dominant or autosomal recessive for mutation of ABCC8 and INS, and autosomal recessive for mutation of GCK and PDX1.

Individuals with autosomal dominant PNDM may have an affected parent or may have a de novo pathogenic variant. Each child of an individual with autosomal dominant PNDM has a 50% chance of inheriting the pathogenic variant.

The parents of a child with autosomal recessive PNDM are obligate heterozygotes and therefore carry one pathogenic variant. Heterozygotes for pathogenic variants in GCK and PDX1 have a mild form of diabetes mellitus known as GCK-familial monogenic diabetes (formerly known as MODY2) and PDX1-familial monogenic diabetes (formerly known as MODY4). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (or of having familial monogenic diabetes), and a 25% chance of being unaffected and not a carrier.

Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) in the family are known.