Wolcott-Rallison syndrome in Iran: a common cause of neonatal diabetes

Abstract

Background Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by neonatal/early-onset non-autoimmune insulin-dependent diabetes, multiple epiphyseal dysphasia and growth retardation. It is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3). We aimed to study the clinical characteristics and frequency of the disease in the Iranian population. Methods We recruited 42 patients who referred to the endocrine and metabolism clinic at Mashhad Imam Reza Hospital with neonatal diabetes. Molecular screening of KCNJ11, INS, ABCC8 and EIF2AK3 was performed at the Exeter Molecular Genetics Laboratory, UK. We calculated the frequency of the disease in 124 patients referred from Iran to the Exeter Molecular Genetics Laboratory for genetic screening and compared it to other countries worldwide. Results We identified seven patients as having Wolcott-Rallison syndrome. Genetic testing confirmed the clinical diagnosis and indicated five novel mutations. Only two patients developed clinical features of the syndrome by 6 months of age. Of all 124 cases of Iranian neonatal diabetes referred to the Exeter Molecular Genetics Laboratory for genetic screening, 28 patients (22.58%) had a recessive mutation in EIF2AK3. Conclusions The results of this study raises awareness of the condition and provides further accurate data on the genetic and clinical presentation of Wolcott-Rallison syndrome in the Iranian population. Our study highlights the importance of genetic testing in patients from consanguineous families with diabetes diagnosed within the first 6 months of life.

Diabetes management in Wolcott-Rallison syndrome: analysis from the German/Austrian DPV database

“…It has been reported that up to 65% of patients with any type of monogenic diabetes present with DKA [25]. Similarly, in other cohorts, 50-70% of individuals with WRS presented with DKA [3,5]. 40% of individuals with WRS in the DPV registry experienced at least one episode of SH during follow-up and 20% of individuals with WRS experienced an episode of SH within the past treatment year.…”

“…in North Africa, Middle East and South Asia, K ATP channel mutations are less common [5]. Instead, in consanguineous populations, EIF2AK3 mutations causing WRS account for up to 25% of PNDM cases [5,9,10]. Consistently, in the DPV cohort all patients for whom this information was available had a migration background, meaning that the patients themselves had immigrated (n = 2) or their parents were born outside the DPV countries (n = 8).…”

“…However, in populations in which inbreeding is frequent, e.g. in North Africa, Middle East and South Asia, K ATP channel mutations are less common [5]. Instead, in consanguineous populations, EIF2AK3 mutations causing WRS account for up to 25% of PNDM cases [5,9,10].…”

“…Several additional features have been described, whose presence and severity vary between patients. These may be present upon diagnosis or develop later during the course of the disease and include recurrent episodes of hepatic failure (in up to 85% of patients [3]), impaired renal function, exocrine pancreatic insufficiency, osteopenia, growth retardation, anaemia, neutropenia associated with recurrent infections, hypothyroidism during stress conditions (referred to as the euthyroid sick syndrome) and developmental delay [4,5]. However, clinical appearance highly varies among patients, even in those sharing the same mutation [3,4,[6][7][8][9].…”

Transient Neonatal Diabetes Mellitus Managed with Continuous Subcutaneous Insulin Infusion (CSII) and Continuous Glucose Monitoring

“…EIF2AK3, which is found on chromosome 2p11.2, encodes a protein kinase Rlike endoplasmic reticulum kinase that is respon sible for βcell development 19) . 1) .…”