Arg924X homozygous mutation in insulin receptor gene in a Tunisian patient with Donohue syndrome

Ons Azzabi; Houweyda Jilani; Imen Rejeb; Nadia Siala; Yasmina Elaribi; Syrine Hizem; Ines Selmi; Sonia Halioui; Olivier Lascols; Lamia Ben Jemaa; Ahmed Maherzi

doi:10.1515/jpem-2015-0232

Article

Arg924X homozygous mutation in insulin receptor gene in a Tunisian patient with Donohue syndrome

Ons Azzabi , Houweyda Jilani , Imen Rejeb , Nadia Siala , Yasmina Elaribi , Syrine Hizem , Ines Selmi , Sonia Halioui , Olivier Lascols , Lamia Ben Jemaa and Ahmed Maherzi

Published/Copyright: March 12, 2016

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 29 Issue 6

Abstract

Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We describe a new case of Donohue syndrome born at 37 weeks’ gestation of unrelated parents and presented with intra-uterine growth retardation, nipple hypertrophy, macropenis, distended abdomen, hirsutism and dysmorphic features. The clinical course showed failure to thrive, and episodes of alternating hypoglycemia and hyperglycemia. Laboratory tests revealed direct hyperbilirubinemia. The diagnosis of Donohue syndrome was established based on the above clinical characteristics and determination of the INSR mutation. He was found to have homozygous nonsense mutation c. 2270 C>T (Arg924X) at exon 14 of the INSR gene. He later developed enterocolitis and died at 3 months old. Prenatal diagnosis was performed for the family via chorionic villous biopsy. We try to explain gastrointestinal dysfunction seen in our patient.

Keywords: Donohue syndrome; homozygous mutation; INSR gene; prenatal diagnosis

Corresponding author: Dr. Imen Rejeb, Department of Medical Genetics, Mongi Slim Hospital, 2046 Sidi Daoud, Tunis, Tunisia, Phone: +21624968503, Fax: +21670939507, E-mail: imen_rejeb@yahoo.fr

aOns Azzabi and Houweyda Jilani contributed equally to this work.

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

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

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. Planchenault D, Martin-Coignard D, Rugemintwaza D, Bah AG, Cosson L, et al. Donohue syndrome or leprechaunism. Arch Pediatr 2014;21:206–10.10.1016/j.arcped.2013.11.016Search in Google Scholar PubMed

2. Vincent-Desplanques D, Faivre-Defrance F, Wémeau JL, Vantyghem MC. Monogenic severe insulin resistance syndromes. La revue de médecine interne 2005;26:866–73.10.1016/j.revmed.2005.04.027Search in Google Scholar PubMed

3. Falik Zaccai TC, Kalfon L, Klar A, Elisha MB, Hurvitz H, et al. Two novel mutations identified in familial cases with Donohue syndrome. Mol Genet Genomic Med 2014;2:64–72.10.1002/mgg3.43Search in Google Scholar PubMed PubMed Central

4. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet 2002;11:1465–75.10.1093/hmg/11.12.1465Search in Google Scholar PubMed

5. Whitehead JP, Soos MA, Jackson R, Tasic V, Kocova M. Multiple molecular mechanisms of insulin receptor dysfunction in a patient with Donohue syndrome. Diabetes 1998;47:1362–4.10.2337/diab.47.8.1362Search in Google Scholar PubMed

6. Reddy SS, Lauris V, Kahn CR. Insulin receptor function in fibroblasts from patients with leprechaunism. Differential alterations in binding, autophosphorylation, kinase activity, receptor-mediated internalization. J Clin Invest 1988;82: 1359–65.10.1172/JCI113739Search in Google Scholar PubMed PubMed Central

7. Kadowaki T, Kadowaki H, Taylor SI. A nonsense mutation causing decreased levels of insulin receptor mRNA: detection by a simplified technique for direct sequencing of genomic DNA amplified by the polymerase chain reaction. Proc Natl Acad Sci USA 1990;87:658–62.10.1073/pnas.87.2.658Search in Google Scholar PubMed PubMed Central

8. Maassen JA, Tobias ES, Kayserilli H, Tukel T, Yuksel-Apak M, et al. Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. J Clin Endocrinol Metab 2003;88:4251–7.10.1210/jc.2003-030034Search in Google Scholar PubMed

9. Odawara M, Kadowaki T, Yamamoto R, Shibasaki Y, Tobe K, et al. Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor. Science 1989;245:66–8.10.1126/science.2544998Search in Google Scholar PubMed

10. Schilling EE, Rechler MM, Grunfeldt C, Rosenberg AM. Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance. Proc Natl Acad Sci 1979;76:5877–81.10.1073/pnas.76.11.5877Search in Google Scholar PubMed PubMed Central

11. Longo N, Langley SD, Griffin LD, Elsas LJ. Two mutations in the insulin receptor gene of a patient with leprechaunism: application to prenatal diagnosis. J Clin Endocrinol Metab 1995;80:1496–501.Search in Google Scholar

12. Drohobyczer D, Bellah R. Polycystic ovaries in leprechaunism. Pediatr Radiol 2010;40:371.10.1007/s00247-009-1379-2Search in Google Scholar PubMed

13. Reddy SS, Kahn CR. Epidermal growth factor receptor defects in leprechaunism. A multiple growth factor-resistant syndrome. J Clin Invest 1989;84:1569–76.10.1172/JCI114334Search in Google Scholar PubMed PubMed Central

14. Park HS, Jin DK, Shin SM, Jang MK, Longo N, et al. Impaired generation of reactive oxygen species in leprechaunism through down regulation of Nox4. Diabetes 2005;54:3175–81.10.2337/diabetes.54.11.3175Search in Google Scholar PubMed

15. Termote JU, Breur JM, De Vroede MA. Hypertrophic cardiomyopathy in Donohue syndrome. Cardiol Young 2015;11:1–4.10.1017/S1047951115002437Search in Google Scholar PubMed

16. Nobile S, Semple RK, Carnielli VP. A novel mutation of the insulin receptor gene in a preterm infant with Donohue syndrome and heart failure. J Pediatr Endocrinol Metab 2012;25:363–6.10.1515/jpem-2011-0448Search in Google Scholar PubMed

17. Odeh R, Alassaf A, Al-Qudah AA. Donohue syndrome: a new case with a new complication. J Pediatr Endocrinol Metab 2015;28:951–4.10.1515/jpem-2014-0405Search in Google Scholar PubMed

18. Caglayan AO, Klammt J, Kiess W, Hatipoglu N, Pfäffle R, et al. A unique case of a patient with partial trisomy 22 and lipodystrophy: is it a new syndrome due to an IGF-IR mutation? Genet Couns 2010;21:187–97.Search in Google Scholar

19. Bashashati M, McCallum RW. Is interstitial cells of Cajal-opathy present in gastroparesis? J Neurogastroenterol Motil 2015;21:486–93.10.5056/jnm15075Search in Google Scholar PubMed PubMed Central

20. Burns AJ. Disorders of interstitial cells of Cajal. J Pediatr Gastroenterol Nutr 2007;45(Suppl 2):S103–6.10.1097/MPG.0b013e31812e65e0Search in Google Scholar PubMed

21. Ordög T, Takayama I, Cheung WK, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes 2000;49:1731–9.10.2337/diabetes.49.10.1731Search in Google Scholar PubMed

22. Horváth VJ, Vittal H, Lörincz A, Chen H, Almeida-Porada G, et al. Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. Gastroenterology 2006;130:759–70.10.1053/j.gastro.2005.12.027Search in Google Scholar PubMed

23. Horváth VJ, Vittal H, Ördög T. Reduced insulin and IGF-I signaling, not hyperglycemia, underlies the diabetes-associated depletion of interstitial cells of Cajal in the murine stomach. Diabetes 2005;54:1528–33.10.2337/diabetes.54.5.1528Search in Google Scholar PubMed

24. Evans PR. Leprechaunism. Arch Dis Child 1955:30:479–83.10.1136/adc.30.154.479Search in Google Scholar PubMed PubMed Central

25. Nakae J, Kato M, Murashita M, Shinohara N, Tajima T, et al. Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism. J Clin Endocrinol Metab 1998;83:542–9.10.1210/jcem.83.2.4602Search in Google Scholar PubMed

26. Takahashi Y, Kadowaki H, Momomura K, Fukushima Y, Orban T, et al. A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism. Diabetologia 1997;40:412–20.10.1007/s001250050695Search in Google Scholar PubMed

27. Backeljauw PF, Alves C, Eidson M, Cleveland W, Underwood LE, et al. Effect of intravenous insulin-like growth factor I in two patients with leprechaunism. Pediatr Res 1994;36:749–54.10.1203/00006450-199412000-00012Search in Google Scholar PubMed

28. Hovnik T, Bratanic N, Podkrajsek KT, Kovač J, Paro D, et al. Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophos- phorylation due to a novel INSR mutation. Eur J Pediatr 2012;171:1901–7.Search in Google Scholar

29. Kawashima Y, Nishimura R, Utsunomiya A, Kagawa R, Funata H, et al. Leprechaunism (Donohue syndrome): a case bearing novel compound heterozygous mutations in the insulin receptor gene. Endocr J 2013;60:107–12.10.1507/endocrj.EJ12-0289Search in Google Scholar

30. Weber DR, Stanescu DE, Semple R, Holland C, Magge SN. Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome. J Pediatr Endocrinol Metab 2014;27:1237–41.10.1515/jpem-2013-0402Search in Google Scholar PubMed PubMed Central

Received: 2015-6-10

Accepted: 2016-1-15

Published Online: 2016-3-12

Published in Print: 2016-6-1

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Articles in the same Issue

https://doi.org/10.1515/jpem-2015-0232

Keywords for this article

Donohue syndrome; homozygous mutation; INSR gene; prenatal diagnosis