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

Samaneh Noroozi Asl 1 , Rahim Vakili 1 , Saba Vakili 1 , Fahimeh Soheilipour 2 , Mahin Hashemipour 3 , Sara Ghahramani 1 , Elisa De Franco 4  and Hanieh Yaghootkar 5
  • 1 Department of Pediatric Disease, Faulty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • 2 Minimally Invasive Surgery Research Center, Rasoul-e-Akram Hospital, Iran University of Medical Science, Tehran, Iran
  • 3 Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  • 4 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
  • 5 Genetics of Complex Traits, University of Exeter Medical School, Medical Research – Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
Samaneh Noroozi Asl
  • Department of Pediatric Disease, Faulty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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, Rahim Vakili
  • Department of Pediatric Disease, Faulty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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, Saba Vakili
  • Department of Pediatric Disease, Faulty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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, Fahimeh Soheilipour
  • Minimally Invasive Surgery Research Center, Rasoul-e-Akram Hospital, Iran University of Medical Science, Tehran, Iran
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, Mahin Hashemipour
  • Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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, Sara Ghahramani
  • Department of Pediatric Disease, Faulty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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, Elisa De Franco
  • Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
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and Hanieh Yaghootkar
  • Corresponding author
  • Genetics of Complex Traits, University of Exeter Medical School, Medical Research – Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
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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.

    • Supplementary Material
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Julier C, Nicolino M. Wolcott-Rallison syndrome. Orphanet J Rare Dis 2010;5:29.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • Export Citation
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The Journal of Pediatric Endocrinology and Metabolism (JPEM) is the only international journal dedicated exclusively to endocrinology in the neonatal, pediatric and adolescent age groups, and publishes the results of clinical investigations in pediatric endocrinology and basic research. JPEM publishes Review Articles, Original Research, Case Reports, Short Communications and Letters to the Editor.

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