IMPE Abstracts

Introduction: Overexpression of the imprinted locus at chromosome 6q24, in which PLAGL1 and HYMAI are located, causes transient neonatal diabetes mellitus (transient NDM, TNDM). Normally, expression of the maternal alleles of PLAGL1 and HYMAI is silenced by differentially methylated region (DMR) methylation. Although it is well known that duplication of 6q24 on the paternal allele causes TNDM (6q24-TNDM), phenotype of paternal triplication of 6q24 has not been defined.

Case Presentation: The patient was a male, born at 29 weeks of gestation by emergency caesarean section due to fetal distress as a second child. His parents and brother had no particular medical history. He exhibited intrauterine growth retardation (IUGR) with a birth weight 607g (-3.8SD). He had no dysmorphic features other than umbilical hernia. He was placed on ventilatory management due to respiratory distress syndrome until day 1, when his blood glucose level increased up to 520 mg/dL. His insulin level was below 0.5 µU/mL and he was started on insulin therapy. At the last follow-up, at 2 years and 6 months, his insulin requirement was 0.1 units/kg/day, with aspart only before each meal, and his HbA1c is 6.7%.

Genetic Analysis: KCNJ11 and ABCC8 sequencing identified no pathogenic variants. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) revealed that there were four copies of the region localized to 6q24.2, with one copy of DMR methylated and three copies in an unmethylated state. MS-MLPA for his father showed the same result as the patient. Single nucleotide polymorphism array demonstrated that the four-copy region was confined to 508 kb, represented as arr [hg19] 6q24.2 (144,235,747-144,743,887)x4, where ZC2HC1B, PLAGL1, HYMAI, SF3B5, STX11 and UTRN are located.

Discussion: This is the first report showing that a paternally derived 6q24 triplication is related with NDM. The identified chromosome region of the present patient has been reported to cause 6q24-TNDM. Compared to the 6q24-TNDM, in which diabetes is usually resolved by at the latest 18 months of age, diabetes of the present patient was not in remission at 2 years 6 months. However, IUGR and umbilical hernia were compatible complication to 6q24-TNDM. In addition, incomplete penetrance of NDM due to paternal 6q24 triplication was observed by the same result of copy number and methylation status of the father. In conclusion, paternal 6q24 triplication results in NDM, which may not be transient.