Presentation: Child with neonatal hypoglycaemia and macrosomia

A baby girl was born at 37 weeks with a birth weight of 4.1kgs. Her blood glucose was two millimoles per litre (2mmol/L) and for five months she required ongoing treatment with diazoxide and chlorothiazide. Her mother had been diagnosed with diabetes at 28 years of age and is insulin treated. She was also born macrosomic and required treatment for low glucose levels post-delivery. The maternal grandfather was diagnosed with type 2 diabetes at the age of 35 and was treated with low doses of sulphonylureas.

• Babies who inherit the affected HNF4A gene from a parent often have a high birth weight (over 4kg, with an average increase in birth weight of 800g) and may have prolonged hyperinsulinaemic hypoglycaemia after birth, which may require treatment for months or years (approximately 10% of cases).
• Flags for an underlying genetic diagnosis of HNF4A maturity onset diabetes of the young (MODY) include:
  • diagnosis of diabetes below the age of 25 in an individual with a parent who also has diabetes;
  • sensitivity to sulphonylureas; and
  • having a child who is born with macrosomia with or without neonatal hypoglycaemia, or the patient themselves having a history of macrosomia as a newborn with a parent who also has diabetes.
• 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.
• The HNF4A gene encodes a protein called a transcription factor, which acts as a switch that turns on and off the expression of other genes in the insulin-secreting beta cells in the pancreas. Pathogenic variants that cause loss of function of the HNF4A gene cause diabetes by reducing the amount of insulin that is produced by the beta cell. Insulin is produced normally in early childhood, but the amount of insulin produced reduces as the patient gets older.
• HNF4A MODY typically results in diabetes presenting in adolescence or early adulthood, although some people may not be diagnosed until middle or old age.
• 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 treatment and convert to sulphonylurea tablet treatment instead.

What do you need to do?

• Enquire about family history, including ages of diabetes diagnosis, any evidence of sulphonylurea sensitivity, macrosomia and neonatal hypoglycaemia in other family members.
• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which gene panel best suits the needs of your patient or family.
  • If you suspect MODY in a child and they have an affected parent, consider genomic testing via the panel R141 (monogenic diabetes) for all affected individuals. You will need to complete and submit a specific test request form.
• As tests are DNA based, an EDTA sample is required.
• Those with HNF4A MODY have a 50% chance of having an affected child who will be at risk of macrosomia and neonatal hypoglycaemia. This means that if your patient or their partner has HNF4A MODY, it is important to seek specialist advice from the diabetes team at the Royal Devon University Healthcare NHS Foundation Trust early on in future pregnancies, because this information can alter how the pregnancy is monitored and cell-free fetal DNA testing may be possible to aid management.
• If molecular genomic testing confirms a diagnosis of HNF4A MODY, you should arrange genomic testing of other family members with a diabetes diagnosis because the information may enable them to change their treatment.
• Information about patient eligibility and test indications was 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.

For clinicians

• DiabetesGenes: Hepatic Nuclear Factor 4 Alpha (HNF4A)
• DiabetesGenes: Training in diabetes subtypes
• National Genomic Test Directory

References:

• Laver TW, Colclough K, Shepherd M and others. ‘The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes’. Diabetes 2016: volume 65, issue 10, pages 3,212–3,217. DOI: 10.2337/db16-0628
• Locke JM, Dustakova P, Colclough K and others. ‘Association of birthweight and penetrance of diabetes in individuals with HNF4A-MODY: A cohort study’. Diabetologia 2022: volume 65, pages 246–259. DOI: 10.1007/s00125-021-05581-6
• Pearson ER, Boj SF, Steele AM and others. ‘Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene’. PLOS Medicine 2007: volume 4, issue 4, page 118. DOI: 10.1371/journal.pmed.0040118
• Pearson ER, Pruhova S, Tack CJ and others. ‘Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection’. Diabetologia 2005: volume 28, pages 878–885. DOI: 10.1007/s00125-005-1738-y
• Shepherd M, Brook AJ, Chakera AJ and others. ‘Management of sulfonylurea-treated monogenic diabetes in pregnancy: Implications of placental glibenclamide transfer’. Diabetic Medicine 2017: volume 34, issue 10, pages 1,332–1,339. DOI: 10.1111/dme.13388

For patients

• DiabetesGenes: Hepatic Nuclear Factor 4 Alpha (HNF4A)