Wolcott-Rallison Syndrome with Novel EIF2AK3 Gene Mutation

©Jo ur nal of Cli ni cal Re se arch in Pe di at ric En doc ri no logy, Pub lis hed by Ga le nos Pub lis hing. Dear Editor, Wolcott-Rallison syndrome (WRS; Online Mendelian Inheritance in Man 226980) is an autosomal recessively inherited disorder characterized by neonatal insulin-dependent diabetes mellitus, skeletal dysplasia (epiphyseal dysplasia), acute hepatic and/or renal dysfunction, exocrine pancreatic insufficiency, neutropenia, developmental delay, and growth retardation (1,2). This syndrome is caused by mutations in the gene encoding eukaryotic translation initiation factor 2a kinase 3 (EIF2AK3), and to date, more than 60 cases have been reported (2,3). A female Kurdish infant at 4 months of age had been diagnosed to have neonatal diabetes when admitted with an episode of diabetic ketoacidosis. Her parents were first-degree cousins. At diagnosis, laboratory findings (reference ranges) were as follows: glucose 492 mg/dL (70-105), C-peptide 0.001 ng/mL (0.9-4.3), insulin 0.2 μIU/mL (1.9-23), and HbA1c 15.2% (4.8-6.0). Her liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT)], thyroid stimulating hormone, thyroxine, blood urea nitrogen, and creatinine levels, and neutrophil count were in normal ranges. Type 1 diabetes-associated autoantibodies (islet cell antibody and glutamic acid decarboxylase antibody) were negative. At the age of eight months, the patient was admitted because of acute hepatic failure (on treatment with a regimen of insulin detemir and insulin lispro injected three times a day). ALT and AST levels (822 U/L and 1559 U/L, respectively) were elevated with no hepatomegaly. Viral hepatitis markers were negative. Additionally, she had neutropenia. During follow-up, with supportive treatment, liver enzymes and absolute neutrophil count returned to normal. No clinical or biochemical evidence of exocrine pancreas insufficiency was observed. At a routine visit at the age of 3 years and 5 months, her height was 90.9 cm (-1.53 standard deviation score) and weight was 11.3 kg (-2.45 standard deviation score). Her HbA1c was 8.69% while taking insulin detemir once a day and insulin lispro three times a day, with a total daily dose of insulin of 1.2 UI/kg. An X-ray survey showed osteopenia, generalized (proximal tibia, distal femur, and proximal phalanges) epiphyseal dysplasia, and tubulation deformities in the carpal bones and phalanges, but there were no abnormal findings in vertebral and pelvic bones (Figure 1). A clinical diagnosis of WRS was corrected by the identification of a novel homozygous nonsense mutation (p.Q333) in exon 5 of the EIF2AK3 gene. [University of Exeter Medical School …