ESPE Abstracts (2018) 89 P-P1-081

ZFP57-associated Transient Neonatal Diabetes is Responsive to Oral Sulfonylurea Treatment

Christina Reinauera, Annemarie Jonassonb, Stefani Harmsena, Pierre Debinskic, Volker Sodittc, Sonia van Afferdend, Ertan Mayatepeka, Carsten Bergmannb, Thomas Meissnera & Sebastian Kummera


aDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Duesseldorf, Germany; bCenter for Human Genetics, Bioscientia, Ingelheim, Germany; cDepartment of Pediatrics, Solingen Municipal Hospital, Solingen, Germany; dPediatric Practice Ufergarten, Solingen, Germany


Background: Transient neonatal diabetes (TNDM) is commonly caused by a methylation loss in the 6q24 region, either in isolation or as multiple-loci demethylation due to ZFP57 gene mutation. TNDM is biphasic; usually resolves after 2–3 months but often recurs between age 4 and late adolescence.

Case: The boy was born at 38 weeks of gestation (birth weight 3340 g, healthy consanguineous Turkish parents, unremarkable pregnancy). He presented at 4 weeks of age with left-sided seizures, and hyperglycaemia of 669 mg/dl (37.1 mmol/l) without ketoacidosis. C-peptide level (0.3 nmol/l) was low, pancreatic autoantibodies negative. Echocardiography, cranial and abdominal ultrasound results were normal. Due to ongoing seizures, phenobarbital therapy was initiated, while the patient exhibited abnormal muscle tone and opisthotonus. DEND (developmental encephalopathy and neonatal diabetes) syndrome was suspected, usually caused by potassium channel mutations. Cerebral MRI showed agenesis of corpus callosum and unspecific periventricular white matter hyperintensities. No other laboratory abnormalities or syndromic features were evident. Intravenous insulin was started (0.25I U/kg per day), stabilizing blood glucose (BG) at around 160–180 mg/dl (9–10 mmol/l). Because of decreasing insulin requirements, insulin was stopped after 7 days, but hyperglycaemia resumed with BG above 300 mg/dl (16.7 mmol/l). After detailed counselling with the parents, oral sulfonylurea (glibenclamide) treatment was started on his 38th day of life, while genetic results were pending. Dosing was gradually increased from 0.1 mg/kg per day to 1.0 mg/kg per day, resulting in good BG response (BG 70–160 mg/dl (3.9–9 mmol/l) without additional insulin applications or signs of ketosis). Pathogenic mutation in INS, ABCC and KCNJ11 were ruled out; however, a homozygous mutation in ZFP57 (c.1372C>G, p.[His458Asp], NM_001109809.2; alternative nomenclature: c.1312C>G, p.[His438Asp]) was found in next-generation-sequencing of all NDM genes, resulting in a loss of methylation in 6q24 as shown by methylation-specific PCR. ZFP57 regulates methylation at several sites in the genome. Thus, multiple-locus demethylation explains the extrapancreatic features with striking clinical overlap to DEND syndrome. This same mutation was described previously in TNDM. A trend toward hypoglycaemia was observed after 10 days of treatment, leading to a dose reduction. Treatment was discontinued after 14 days (52th day of life) due to diabetes remission.

Conclusion: While TNDM cases due to K-ATPase channel mutations (ABCC and KCNJ11) are routinely treated with oral sulfonylurea, this is the first description of successful glibenclamide treatment in ZFP57-associated TNDM. Furthermore, it underlines the benefits of early broad genetic differential diagnosis in neonatal diabetes.