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At a glance:

  • A patient with early onset diabetes and an affected parent could have maturity-onset diabetes of the young (MODY). Genomic testing (if the patient meets the criteria for genomic testing) could identify a pathogenic variant in the HNF4A gene.
  • Individuals who inherit a variant in the HNF4A gene often have a high birth weight (over 4kg) and may have needed treatment for low blood sugars early in life (neonatal hypoglycaemia).
  • HNF4A MODY is best treated with low doses of sulphonylureas. However, with increasing age, individuals may require a combination of tablets and insulin to stop deterioration in blood glucose.
  • Alert! Those with HNF4A MODY have a 50% chance of having an affected child, who will be at risk of macrosomia and transient neonatal hypoglycaemia due to hyperinsulinism. This can alter monitoring and testing options during pregnancy, and it is therefore important to seek specialist advice from the Exeter Clinical Laboratory.

 

 

Example clinical scenario

A 48-year-old man transfers to your care having recently moved into the area. He was diagnosed with diabetes aged 28 and has been treated with tablets ever since. His BMI is 25. His mother had diabetes and was also treated with tablets. His first child was born at term with a birth weight of 3.6kg and no problems. His second child was born at 38 weeks’ gestation with a birth weight of 4.2kg and had transient neonatal hyperinsulinaemic hypoglycaemia, which required treatment with diazoxide for six months.

Identifying those at risk of a genetic condition

  • Flags for an underlying genetic diagnosis of HNF4A MODY include:
    • diagnosis of diabetes below the age of 25 in an individual with a parent or child with a diagnosis of diabetes;
    • sensitivity to sulphonylureas; and
    • having a child who is born with macrosomia and neonatal hypoglycaemia or having a history of it as a newborn with a parent who has diabetes.
  • HNF4A MODY typically results in diabetes presenting in childhood or early adulthood, although some people may not be diagnosed until middle or old age.
  • HNF4A MODY follows an autosomal dominant inheritance pattern, meaning that first-degree relatives have a 50% chance of being affected. This means that diabetes is usually identified in two or more generations.
  • Individuals with HNF4A MODY may be sensitive to sulphonylureas, although as the diabetes progresses additional medication may be needed. Those with HNF4A MODY taking insulin from diagnosis of diabetes prior to genomic testing may be able to stop insulin and convert to sulphonylurea tablet treatment instead.
  • HNF4A MODY can lead to macrosomia and neonatal hypoglycaemia in affected babies, so specialist advice is required during pregnancy (irrespective of whether the mother or father has a pathogenic HNF4A variant) and non-invasive prenatal genomic testing (NIPT) using cell-free fetal DNA (cffDNA) to aid management may be possible.

What do you need to do?

  • Enquire about family history, including ages of diabetes diagnosis, any evidence of sulphonylurea sensitivity, macrosomia and neonatal hypoglycaemia.
  • Enter details into the MODY probability calculator.
  • If indicated by the MODY probability calculator, refer for genomic testing.
  • If molecular genomic testing confirms a diagnosis of HNF4A MODY, arrange genomic testing for other family members with a diabetes diagnosis, as this may enable them to change treatment.
  • Alert the Exeter Clinical Laboratory to current pregnancies in HNF4A families early, as cffDNA testing to aid management may be possible.
  • 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 19/06/2023
  • Next review due: 19/06/2024
  • Authors: Professor Maggie Shepherd
  • Reviewers: Dr Maarit Brooks, Professor Kevin Colclough, Dr Asma Hamad