Background: Wolcott-Rallison syndrome (WRS) is a rare recessively inherited disorder characterized by insulin-dependent diabetes and multiple epiphyseal dysplasia. The disease is also characterized by recurrent episodes of hepatitis or hepatic failure, growth retardation and developmental regression. WRS is caused by biallelic mutations in EIF2AK3, encoding the eukaryotic translation initiation factor-2 kinase 3 (IEF2AK3). EIF2AK3 regulates the synthesis of unfolded proteins in the endoplasmic reticulum and is involved in the differentiation of pancreatic islet beta cell progenitors. To date, several mutations from all over the world have been described in the EIF2AK3 gene; however, no case report has been described from the State of Qatar.
Objective(s): To describe a complex case of WRS in a Qatari patient.
Case report: This patient presented with permanent neonatal diabetes (PNDM) and subsequent autoimmune liver disease requiring a liver transplant, progressive left hemispheric cerebral atrophy of unknown etiology, severe seizure disorder requiring multiple anticonvulsants, sodium losing nephropathy, and EBV viremia.
Methods: All exons (117) of the EIF2AK3 gene were amplified by PCR. The amplified products were then sequenced using ABI 3500XL sequencers and analyzed for sequence variations. The variations significance was determined by comparison with wild type sequences, previously reported mutations, and correlation with the eukaryotic translation initiation factor2-alpha kinase 3 protein structure.
Results: DNA analysis revealed a c.1566_1569delGAAA in exon 9 of the EIF2AK3 gene. This four-nucleotide deletion causes a frameshift and resulting in aberrant mRNA processing. This exact change has been previously published as an EIF2AK3 mutation. The patient is homozygous for this mutation. Analysis of DNA derived from the father and mother reveals a heterozygous EIF2AK3 exon 9 deletion. EIF2AK3 analysis was restricted to exon 9 and flanking sequences.
Conclusion: This is the first Qatari patient to be described with a complex phenotype of Wolcott-Rallison syndrome (WRS). The cause of the left hemispheric cerebral atrophy and the nephropathy are not known in this patient and expand the clinical phenotype of patients with WRS.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology