Successful transition to sulfonylurea for relapsed monogenic diabetes due to rare 6q23.3 duplication

Hassan D.; Allen DB.; Chen M.

doi:10.1530/ey.22.2.10

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 2.10 | DOI: 10.1530/ey.22.2.10

ESPEYB25 2. Antenatal and Neonatal Endocrinology Hyperinsulinemic Hypoglycemia, Neonatal Diabetes (4 abstracts)

2.10. Successful transition to sulfonylurea for relapsed monogenic diabetes due to rare 6q23.3 duplication

Hassan D. , Allen DB. & Chen M.

JCEM Case Rep 2024 Oct 16;2(10):luae180. doi: 10.1210/jcemcr/luae180

Brief Summary: This paper describes a female born SGA with transient neonatal diabetes (TNDM)¹due to a 6q23.3 duplication. It is one of only a few published cases, and the first case who transitioned to sulfonylurea when diabetes relapsed. She was treated with insulin until age 4 months and then again after relapse as an adolescent. At age 15y 3m, she developed diabetic ketoacidosis and was negative for antibodies to GAD-65, IA2 and ZN transporter 8. After a 3-month period on insulin, she was successfully transitioned to glyburide and has maintained a normal HbA1c (5.5-5.7) on this medication during the 17 months of follow-up to date. She had global developmental delay and was delayed scholastically by 8 years. She had several facial dysmorphisms, but no macroglossia or umbilical hernia. Whole exome sequencing or a targeted monogenic diabetes gene panel was not performed. Interestingly, when her 6q23.3 duplication was diagnosed in infancy (in 2007), it was noted as a variant of unknown significance.

The most frequent cause (60-70%) of TNDM is over expression of normally imprinted genes within a critical region on 6q. The most common mechanism is paternal UPD of chromosome 6 followed by a 6q24 duplication and rare hypomethylation of the maternal genes in the TNDM locus.

The critical 6q region for TNDM is 6q23-24 and implicates the paternally expressed PLAGL1 (pleiomorphic adenoma gene-like 1), and HYMAI (hydatidiform mole associated imprinted,within the same domain). Animal data and patient reports suggest that with these duplications, beta cells retain insulin reserves but have decreased sensitivity to glucose.

Main points from this case are that sulfonylureas may be useful for treating both TNDM and relapsing diabetes in cases of 6q23-24 duplications, although the duplication subtypes, additional genetic loci and epigenetic factors may modify the response.

Reference: 1. Greeley SAW et al. ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2022 Dec;23(8):1188-1211. doi: 10.1111/pedi.13426.