ESPE Abstracts (2014) 82 P-D-1-1-58

A leu402pro Mutation of the Non-hla Gene il18rap in Aggressive Neonatal Type 1 Diabetes Mellitus

Mirjam Dirlewangera, Jean-Louis Blouinb, Jeremy Bevillarda,b, Federico Santonia,b & Valérie Schwitzgebela


aPediatric Endocrine and Diabetes Unit, Children’s University Hospital, Geneva, Switzerland; bGenetic Medicine and Development, University Medical Center, Geneva, Switzerland


Background: Neonatal diabetes mellitus is defined by severe hyperglycemia appearing before 6 months of age. It occurs in about one in 200 000 live births and most cases are known to be of monogenic origin. Classical autoimmune type 1 diabetes mellitus (DM) is exceptional in this age group.

Objective and hypotheses: Recently non-HLA type 1 DM susceptibility genes, such as IL18RAP, influencing the rate of progression to diabetes among children with multiple autoantibodies have been described.

Method: We report a case of severe ketoacidosis in a 3 months old boy, born at term with a normal birth weight.

Results: HbA1c was 6.4%. The anti-GAD65 antibody (14.9 EI/ml, n<10) was positive and increased to 328 IE/ml after 2 months. The mother’s islet autoantibodies were negative. Pancreatic ultrasound and fecal elastasis level were within normal limits, as well as thyroid function tests. HLA genotyping confirmed a high risk for diabetes with homozygosity for HLA DR3-DQ2. No mutation was found by direct sequencing of KCNJ11, ABCC8, INS, and FOXP3 genes. Whole exome analysis revealed a highly damaging p.Leu402Pro mutation of IL18RAP.

Conclusion: We concluded that our patient has a type 1 DM, based on increasing anti-GAD antibodies and high-risk HLA genotyping. A monogenic form of neonatal DM secondary to a KATP channel, insulin or FOXP3 mutation could be excluded. This case illustrates an extremely early and rapid onset of diabetes in infancy by the combined presence of a novel mutation in the type 1 DM susceptibility gene IL18RAP and a high-risk HLA genotype. The exact functional effect of this Leu402Pro mutation has not been analyzed yet, but could involve IFNγ production. The identification of this characteristic signature of rapid progression in a very young child with an islet autoantibody-positive type 1 DM supports the hypothesis that characteristic antibodies and gene profiles could further help to identify high-risk phenotypes.

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