Presentation: Child with neonatal diabetes and developmental delay

A family attends clinic concerned because their five-year-old son’s development is delayed. He sat at one year, was walking at two years and, at the age of five, is vocalising sounds but not single words. He developed diabetes at six weeks and has been insulin treated ever since. There is no family history of diabetes.

• Anyone diagnosed with diabetes below the age of six months should be offered genomic testing, whatever their current age. In itself, diabetes diagnosed at this stage of life indicates that a referral for genomic testing is required; however, in some cases the diabetes may also be associated with other features, the presence of which should also prompt testing:
  • low birth weight (indicating insulin deficiency in utero);
  • developmental delay; and
  • other medical problems, such as heart or skeletal anomalies or liver dysfunction.

• 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 those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• All patients diagnosed with diabetes at under nine months of age are eligible for genomic testing under the R143 neonatal diabetes panel. However, pathogenic variants are most commonly found in those diagnosed at under six months of age.
  • Initial testing for the most common genetic causes (KCNJ11, ABCC8 and INS) will be carried out first.
  • If results of these initial investigations are negative, the laboratory will proceed with further testing for imprinting conditions, which can cause transient neonatal diabetes.
  • If results of these further tests are also negative, full-panel testing for neonatal diabetes will need to be carried out via whole genome sequencing.
• Testing of parental samples is often key to obtaining a genetic diagnosis, since the majority of variants causing neonatal diabetes are found to have arisen spontaneously (de novo) in patients. When requesting tests, include samples from both parents whenever possible – whether affected or unaffected.
• As the relevant tests are DNA-based, an EDTA sample (purple-topped tube) is required.
• If a pathogenic variant in KCNJ11 or ABCC8 is identified, there may be significant implications for treatment because such cases are optimally managed on high doses of sulphonylureas. In these cases, specialist guidance should be sought from the diabetes team at the Royal Devon and Exeter NHS Foundation Trust.
• 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: About neonatal diabetes
• DiabetesGenes: Genetic testing for neonatal diabetes
• DiabetesGenes: Neonatal diabetes caused by mutations in KCNJ11 or ABCC8
• NHS England: National Genomic Test Directory

References:

• De Franco E, Flanagan SE, Houghton JAL and others. ‘The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study’. The Lancet 2015: volume 386, issue 9997, pages 957–963. DOI: 10.1016/S0140-6736(15)60098-8
• Docherty LE, Kabwama S, Lehmann A and others. ‘Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients’. Diabetologia 2013: volume 56, issue 4, pages 758–776. DOI: 10.1007/s00125-013-2832-1
• Flanagan SE, Patch A-M, Mackay DJG and others. ‘Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood’. Diabetes 2007: volume 56, issue 7, pages 1,930–1,937. DOI: 10.2337/db07-0043
• Støy J, De Franco E, Honggang Y and others. ‘In celebration of a century with insulin – Update of insulin gene mutations in diabetes’. Molecular Metabolism 2021: volume 52. DOI: 10.1016/j.molmet.2021.101280

For patients

• DiabetesGenes: About neonatal diabetes
• Facebook: Neonatal diabetes family group