THE 3rd W522X MUTATION IN EIF2AK3 GENE FROM TURKEY: A NEW PATIENT WITH WOLCOTT-RALLISON SYNDROME

INTRODUCTIONWolcott-Rallison syndrome (WRS, OMIM #226980) is a rare autosomal recessive disorder, characterized by neonatal/early-onset non-autoimmune insulin-dependent diabetes mellitus associated with skeletal dysplasia and growth retardation. Diabetes mellitus appearing before six months of age (frequently acute presentation of severe diabetic ketoacidosis at disease onset) (6,9,10) and skeletal dysplasia diagnosed within the 1 st or 2nd year of life are characteristic. Hepatic dysfunction appearing as recurrent acute liver failure is the third most frequently observed feature of the syndrome which seems to be another characteristic feature of the syndrome (3, 6, 9). Liver disease is important because it is recently understood that patients well-treated for diabetes almost always die because of acute liver failure. Other frequent clinical manifestations are renal dysfunction, mental retardation, cardiac abnormalities, exocrine pancreatic dysfunction, primary hypothyroidism and neutropenia (1,2,3,6,9,10,11,14,15).It is a rare disease although now recognised as the most frequent cause of neonatal/early onset diabetes mellitus in patients with consanguineous parents (9). The exact prevalence of this rare syndrome is unknown probably because patients may die due to acute multiorgan failure before expressing the characteristic features of the syndrome or because the association is not evident in younger ages (6). Diagnosis should be thought in infants with permanent neonatal diabetes mellitus (PNMD) with a family history of consanguinity and/or neonatal diabetes mellitus especially when there is skeletal dysplasia and/or additional clinical findings (9).WRS is caused by mutations in the EIF2AK3 gene encoding the PERK (protein kinase RNA-like endoplasmic reticulum kinase) enzyme (2). PERK is a membrane protein located in the endoplasmic reticulum (ER) which plays a key role in detecting and initiating the cellular response to ER stress. Failure of appropriate PERK response results in accumulation of misfolded proteins, which leads to cell damage and apoptosis (5,14). EIF2AK3 knockout mouse studies demonstrated that PERK is required for pancreatic beta cell development during fetal and early neonatal development (15) and that diabetes and skeletal dysplasia are due to loss of PERK expression in pancreatic beta cells (7) and osteoblasts (12).More cases of WRS have been reported in the literature in the past 15 years, so we know more about its clinical spectrum, pathophysiology, and genetics. Many mutations have been published in the EIF2AK3 gene in WRS patients which are either nonsense or frameshift mutations resulting in premature termination of the protein, or missense mutations located in the kinase domains of the protein.The clinical variability seems to be independent from the nature of the EIF2AK3 mutations, with a possible exception of older age at onset and longer survival (9,10). Other factors responsible for the disease variability may include other genes, exposure to environmental factors and disease management (6).Among the reported mutations, some of them seem to be confined to a country (4).This is the third family with the same mutation from Turkey and W522X mutation has not been reported from another country till now. In this report we describe clinical features of a WRS patient with W522X mutation in the EIF2AK3 gene, comparatively with the previously reported two families having the same mutation. Then we compare these three families with the other patients reported to date.CASE REPORTThe patient is an 8-year-old Turkish girl who was presented to Gazi University Hospital, Medical Genetics Department with PNMD, primary hypothyroidism, thalassemia minor and developmental delay.Bom to first-cousin parents, she is the second of five children in the family. Family history is positive for thalassemia minor in the father, mother, 3rd and 4th children and for thalassemia major in the fifth child who had a bone marrow transplant. …