Monogenic Forms of Diabetes

Monogenic forms of diabetes, previously termed maturity-onset diabetes of youth (MODY) and neonatal diabetes, are not considered type 1 or type 2 (although they are sometimes mistaken for them) and are uncommon (< 1 to 5% of non-autoimmune cases). Monogenic forms are caused by genetic defects that are inherited in an autosomal dominant pattern, so patients typically have one or more affected family members. Unlike types 1 and 2, there is no autoimmune destruction of beta-cells or insulin resistance. Onset is usually before age 25 years. Neonatal diabetes appears within the first 6 months of life.

In monogenic forms of diabetes, the underlying defect depends on the type. The most common types are caused by defects in transcription factors that regulate pancreatic beta-cell function (eg, hepatic nuclear factor 1-alpha [HNF-1-α]). In these types, insulin secretion is impaired but not absent, there is no insulin resistance, and hyperglycemia worsens with age. Another type of monogenic diabetes is caused by a defect in the glucose sensor, glucokinase. With glucokinase defects, insulin secretion is normal but glucose levels are regulated at a higher set point, causing fasting hyperglycemia that worsens minimally with age.

Monogenic diabetes in children, including MODY and neonatal diabetes, typically presents at a young age (< 6 months for neonatal diabetes) with mild to moderate hyperglycemia (> 150 to 200 mg/dL [8.3 to 11.1 mmol/L]), often without ketoacidosis (1). Children generally do not have obesity, lack pancreatic autoantibodies, and may not require insulin initially due to preserved ). Children generally do not have obesity, lack pancreatic autoantibodies, and may not require insulin initially due to preservedinsulin production. Patients do not typically have signs of insulin resistance (eg, acanthosis nigricans)

Neonatal diabetes can be associated with growth and developmental issues. Unlike type 1 diabetes, symptoms are often subtle, and clinical features vary depending on the specific genetic mutation.

The diagnosis should be considered in children with a strong family history of diabetes but who lack typical features of type 2 diabetes.

Genetic testing is available to confirm monogenic diabetes. This testing is important because some types of monogenic diabetes can progress with age. Some patients with monogenic diabetes will have a family history suggesting an autosomal dominant inheritance pattern (ie, one parent and multiple relatives on that parent's side affected). Additionally, some forms of monogenic diabetes are associated with kidney or genitourinary abnormalities.