ESPE Abstracts

Background: GLIS3 is a transcription factor involved in the development of pancreatic β-cells, the thyroid, eyes, liver and kidneys. In the pancreas, GLIS3 is expressed at various stages of ductal and endocrine cell development, and is a critical regulator of β-cell development and insulin expression. Mutations in GLIS3 have been recently described as a rare cause of neonatal diabetes and congenital hypothyroidism (CH), reported in only 20 patients to date.

Case report: Two term small for gestational age non-identical twins (male and female), were born to first-cousin parents. Both developed marked hyperglycemia in the first 24 h of life. During their first weeks, they were diagnosed with primary CH, bilateral glaucoma, mild cholestasis, and polycystic kidneys. Regular IV insulin administration was started and continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) were initiated at 2 weeks of age. L-T₄ therapy was started on the 5^th day of life and bilateral eye trabeculotomy was performed at 1.5 months. After the first month, the best diabetes control was achieved with CSII using insulin Humalog diluted 1:10 (10 U/mL). The combination of neonatal diabetes with CH, kidney cysts, cholestasis and glaucoma suggested the diagnosis of a GLIS3 mutation; this was confirmed by molecular analysis. A novel homozygous nonsense mutation (c.2392C>T, p.Gln798Ter) located in exon 9 in both twins, and the heterozygous mutation in the parents were identified. Currently, at the age of 1 year, both twins have mild motor retardation and low weight gain. Kidney cysts have disappeared, liver function tests and intraocular pressure are normal and their thyroid function tests are controlled with L-T₄ dose of 250–300 μg/week. HbA1c is 7.7% (male) and 8.5% (female), with a daily insulin dose of 0.4–0.5 unit/kg.

Conclusions: We report a novel GLIS3 mutation in non-identical twins with a combination of neonatal diabetes, CH and glaucoma. We will discuss the challenges in managing neonatal diabetes, and show that the combination of CSII and CGM is the best way to achieve diabetes control in neonates. Our report highlights the importance of early molecular diagnosis for the management of, and genetic consultation in neonatal diabetes.