Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter May 29, 2019

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

Samaneh Noroozi Asl, Rahim Vakili, Saba Vakili, Fahimeh Soheilipour, Mahin Hashemipour, Sara Ghahramani, Elisa De Franco and Hanieh Yaghootkar

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.

Acknowledgments

This work was supported by the Wellcome Trust [108101/Z/15/Z]. H.Y. was funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). We thank all the families and their referring clinicians. We thank Dr. Samuel E Jones, University of Exeter, for proofreading this manuscript.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Iafusco D, Stazi MA, Cotichini R, Cotellessa M, Martinucci ME, et al. Permanent diabetes mellitus in the first year of life. Diabetologia 2002;45:798–804.10.1007/s00125-002-0837-2Search in Google Scholar

2. Edghill EL, Dix RJ, Flanagan SE, Bingley PJ, Hattersley AT, et al. HLA genotyping supports a nonautoimmune etiology in patients diagnosed with diabetes under the age of 6 months. Diabetes 2006;55:1895–8.10.2337/db06-0094Search in Google Scholar

3. Iafusco D, Massa O, Pasquino B, Colombo C, Iughetti L, et al. Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births. Acta Diabetol 2012;49:405–8.10.1007/s00592-011-0331-8Search in Google Scholar

4. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004;350:1838–49.10.1056/NEJMoa032922Search in Google Scholar

5. Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, et al. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 2006;15:1793–800.10.1093/hmg/ddl101Search in Google Scholar

6. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006;355:456–66.10.1056/NEJMoa055068Search in Google Scholar

7. Stoy J, Edghill EL, Flanagan SE, Ye H, Paz VP, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 2007;104:15040–4.10.1073/pnas.0707291104Search in Google Scholar

8. De Franco E, Flanagan SE, Houghton JA, Lango Allen H, Mackay DJ, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet 2015;386:957–63.10.1016/S0140-6736(15)60098-8Search in Google Scholar

9. Globa E, Zelinska N, Mackay DJ, Temple KI, Houghton JA, et al. Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment. J Pediatr Endocrinol Metab 2015;28:1279–86.10.1515/jpem-2015-0170Search in Google Scholar

10. Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, et al. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab 2009;94:4162–70.10.1210/jc.2009-1137Search in Google Scholar

11. Zhang W, Feng D, Li Y, Iida K, McGrath B, et al. PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab 2006;4:491–7.10.1016/j.cmet.2006.11.002Search in Google Scholar

12. Julier C, Nicolino M. Wolcott-Rallison syndrome. Orphanet J Rare Dis 2010;5:29.10.1186/1750-1172-5-29Search in Google Scholar

13. Hosseini-Chavoshi M, Abbasi-Shavazi MJ, Bittles AH. Consanguineous marriage, reproductive behaviour and postnatal mortality in contemporary Iran. Hum Hered 2014;77:16–25.10.1159/000358403Search in Google Scholar

14. Senee V, Vattem KM, Delepine M, Rainbow LA, Haton C, et al. Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 2004;53:1876–83.10.2337/diabetes.53.7.1876Search in Google Scholar

15. Ozbek MN, Senee V, Aydemir S, Kotan LD, Mungan NO, et al. Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. Pediatr Diabetes 2010;11:279–85.10.1111/j.1399-5448.2009.00591.xSearch in Google Scholar

16. Brickwood S, Bonthron DT, Al-Gazali LI, Piper K, Hearn T, et al. Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 2003;40:685–9.10.1136/jmg.40.9.685Search in Google Scholar

17. Dias RP, Buchanan CR, Thomas N, Lim S, Solanki G, et al. Os odontoideum in Wolcott-Rallison syndrome: a case series of 4 patients. Orphanet J Rare Dis 2016;11:14.10.1186/s13023-016-0397-zSearch in Google Scholar

18. Mihci E, Turkkahraman D, Ellard S, Akcurin S, Bircan I. Wolcott-Rallison syndrome due to a novel mutation (R491X) in EIF2AK3 gene. J Clin Res Pediatr Endocrinol 2012;4:101–3.10.4274/Jcrpe.619Search in Google Scholar

19. Iyer S, Korada M, Rainbow L, Kirk J, Brown RM, et al. Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta Paediatr 2004;93:1195–201.10.1111/j.1651-2227.2004.tb02748.xSearch in Google Scholar


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2018-0434).


Received: 2018-10-09
Accepted: 2019-04-17
Published Online: 2019-05-29
Published in Print: 2019-06-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

Scroll Up Arrow