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Primary hypothyroidism and nipple hypoplasia in a girl with Wolcott–Rallison syndrome

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Abstract

Wolcott–Rallison syndrome (WRS), caused by mutation in the EIF2AK3 gene encoding the PERK enzyme, is the most common cause of permanent neonatal diabetes mellitus (PNDM) in consanguineous families and isolated populations. Besides PNDM, it also includes skeletal abnormalities, liver and renal dysfunction, and other inconsistently present features. We present two siblings, who are WRS patients, and are Albanians from Kosovo born to unrelated parents. The older sister presented with PNDM, exocrine pancreatic insufficiency, short stature, microcephaly, normocytic anemia, delay in speech development, skeletal abnormalities, primary hypothyroidism, and hypoplastic nipples. Sequencing of the EIF2AK3 gene identified a homozygous mutation R902X in exon 13. The younger brother was diagnosed with PNDM and died from hepatic failure suggesting that he has been suffering from WRS as well. Including one previously reported patient from Kosovo carrying the same homozygous mutation, there are three WRS patients from this very small, ethnically homogenous region suggesting founder effect in this population. Conclusion: We postulate that thyroid hypoplasia with primary subclinical hypothyroidism already reported in two WRS patients and nipple hypoplasia could also be the phenotypic reflection of the mutation of pleiotropic EIF2AK3 gene in secretory cells.

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References

  1. Bin-Abbas B, Al-Mulhim A, Al-Ashwal A (2002) Wolcott–Rallison syndrome in two siblings with isolated central hypothyroidism. Am J Med Genet 111(2):187–190. doi:10.1002/ajmg.10495

    Article  PubMed  Google Scholar 

  2. Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat Genet 25(4):406–409. doi:10.1038/78085

    Article  CAS  PubMed  Google Scholar 

  3. Ersoy B, Ozhan B, Kiremitci S, Rubio-Cabezas O, Ellard S (2013) Primary hypothyroidism: an unusual manifestation of Wolcott–Rallison syndrome. Eur J Pediatr. doi:10.1007/s00431-013-2110-8

  4. Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, Hussain K, Balafrej A, Deeb A, Buchanan CR, Jefferson IG, Mutair A, Hattersley AT, Ellard S (2009) Wolcott–Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab 94(11):4162–4170. doi:10.1210/jc.2009-1137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Sequeira S, Ranganathan A, Adam A, Iglesias B, Farias E, Aguirre-Ghiso J (2007) Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation. PLoS One 2(7):e615

    Article  PubMed Central  PubMed  Google Scholar 

  6. Stoss H, Pesch HJ, Pontz B, Otten A, Spranger J (1982) Wolcott–Rallison syndrome: diabetes mellitus and spondyloepiphyseal dysplasia. Eur J Pediatr 138(2):120–129

    Article  CAS  PubMed  Google Scholar 

  7. Ulianich L, Garbi C, Treglia AS, Punzi D, Miele C, Raciti GA, Beguinot F, Consiglio E, Di Jeso B (2008) ER stress is associated with dedifferentiation and an epithelial-to-mesenchymal transition-like phenotype in PC Cl3 thyroid cells. J Cell Sci 121(Pt 4):477–486. doi:10.1242/jcs.017202

    Article  CAS  PubMed  Google Scholar 

  8. Wolcott CD, Rallison ML (1972) Infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. J Pediatr 80(2):292–297

    Article  CAS  PubMed  Google Scholar 

  9. Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K, Cavener DR (2002) The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 22(11):3864–3874

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener DR (2006) PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab 4(6):491–497. doi:10.1016/j.cmet.2006.11.002

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to Sian Ellard and Elisabeth Young, Royal Devon, and Exeter National Health Service Healthcare Trust for molecular genetic analysis. We also thank Oscar Rubio-Cabezas for useful discussions.

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The authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pediatrics, University Hospital Centre Zagreb, Kišpatićeva 12, Zagreb, 10000, Croatia

    Anita Špehar Uroić

  2. Pediatric Clinic Department of Endocrinology, University Clinical Center Kosovo, Prishtina, 10000, Kosovo

    Vjosa Mulliqi Kotori

  3. School of Medicine, Department of Pediatrics, University Hospital Center Zagreb, Zagreb, 10000, Croatia

    Nataša Rojnić Putarek & Miroslav Dumić

  4. School of Medicine, Clinical Institute of Laboratory Diagnostic, University Hospital Center Zagreb, Zagreb, 10000, Croatia

    Vesna Kušec

Authors
  1. Anita Špehar Uroić
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  2. Vjosa Mulliqi Kotori
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  3. Nataša Rojnić Putarek
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  4. Vesna Kušec
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  5. Miroslav Dumić
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Correspondence to Anita Špehar Uroić.

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Špehar Uroić, A., Mulliqi Kotori, V., Rojnić Putarek, N. et al. Primary hypothyroidism and nipple hypoplasia in a girl with Wolcott–Rallison syndrome. Eur J Pediatr 173, 529–531 (2014). https://doi.org/10.1007/s00431-013-2189-y

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  • DOI: https://doi.org/10.1007/s00431-013-2189-y

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