Presentation: Patient with young-onset diabetes and an affected parent: HNF1A MODY

A 24-year-old woman presents with diabetes with polydipsia, polyuria, glycosuria and a haemoglobin A1C (HbA1c) of 58 millimoles per mole (mmol/mol). She is otherwise fit and healthy, with a BMI of 23. She mentions that her father was diagnosed with diabetes at the age of 25, that he was insulin treated and that he had a myocardial infarction (MI) at the age of 50. In addition, her paternal grandmother was diagnosed with diabetes at the age of 32 and was treated with oral medication.

Flags for an underlying genetic diagnosis of HNF1A MODY are listed below.

• Diagnosis of diabetes in an individual who is under 25 and has a parent or child with diabetes (typically three or more generations affected) in an autosomal dominant inheritance pattern.
• Several family members diagnosed young who do not require insulin treatment or have evidence of endogenous insulin production – for example, they are C-peptide positive more than three years post-diagnosis.
• Evidence of sensitivity to sulphonylureas in other family members with diabetes, such as hypoglycaemia on standard doses (individuals with HNF1A MODY are sensitive to sulphonylureas).
• Family history of early, possibly fatal MI:
  • HNF1A MODY can result in increased cardiovascular risk with early MI, despite ‘normal’ high-density lipoprotein (HDL) levels (the HDL is typically large, buoyant and non-cardioprotective).
• Negativity of all three pancreatic antibodies (GAD, IA2 and ZnT8).
• Evidence of low renal threshold for glucose (those with HNF1A MODY have a low renal threshold for glucose, and glycosuria is common – often presenting before the diabetes diagnosis).

• Enquire about family history: ask particularly about any evidence of sulphonylurea sensitivity in other family members.
• Enter the patient’s details into the MODY probability calculator.
• Test for all three pancreatic antibodies (GAD, IA2 and ZnT8) in insulin-treated individuals and, if negative, refer for genomic testing.
• If molecular genomic testing confirms a diagnosis of HNF1A MODY, arrange genomic testing for other family members with a diabetes diagnosis, as this may enable them to change treatment.
• HNF1A MODY is best treated with low doses of sulphonylureas. Insulin is typically not required, although a background dose of insulin in addition to other oral medication may be needed in those with a long diabetes duration, because the diabetes is progressive.
• For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

• Diabetic Genes: Genetic test referral forms
• Diabetes Genes: Hepatic Nuclear Factor 1 Alpha (HNF1A)
• Diabetes Genes: Training in diabetes subtypes
• Exeter Diabetes: MODY probability calculator

References:

• Pearson ER, Starkey BJ, Powell RJ and others. ‘Genetic cause of hyperglycaemia and response to treatment in diabetes’. The Lancet 2003: volume 362, issue 9,392, pages 1,275–1,281. DOI: 10.1016/S0140-6736(03)14571-0
• Steele AM, Shields BM, Shepherd M and others. ‘Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene’. Diabetic Medicine 2010: volume 27, issue 2, pages 157–161. DOI: 10.1111/j.1464-5491.2009.02913.x
• Stride A, Ellard S, Clark P and others. ‘β-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1α mutation carriers’. Diabetes Care 2005: volume 28, issue 7, pages 1,751­–1,756. DOI: 10.2337/diacare.28.7.1751

For patients

• Diabetes Genes: Hepatic Nuclear Factor 1 Alpha (HNF1A)