European Journal of Pediatrics

, Volume 170, Issue 5, pp 661–666 | Cite as

Destructive pulmonary staphylococcal infection in a boy with hyper-IgE syndrome: a novel mutation in the signal transducer and activator of transcription 3 (STAT3) gene (p.Y657S)

  • Jin-yan Liu
  • Qiang Li
  • Ting-ting Chen
  • Xia Guo
  • Jiao Ge
  • Li-xing Yuan
Short Report

Abstract

Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder, characterized by eczema, recurrent skin and lung infections, and significantly elevated serum IgE level. It was previously diagnosed based on clinical manifestations and laboratory markers that were not specific to the disease. Recent studies have demonstrated that mutations in signal transducer and activator of transcription 3 (STAT3) cause the autosomal dominant or sporadic HIES, which make the disease definitively characterized at molecular level. Here, we reported a 3-year old Chinese boy with neonatal-onset rash and multiple serious Staphylococcus aureus infections including recurrent skin abscesses, liver abscess, sepsis, and destructive pulmonary infection (pneumonia, multiple pulmonary abscesses, pyopneumothorax, and finally, pneumatocele). Genetic study revealed a heterozygous mutation in exon 21 of STAT3 gene (g.66583 A > C, c.1970A > C) in the boy, which resulted in a substitution of tyrosine at the amino acid position 657 to serine (p.Y657S) in the Src homology 2 (SH2) domain of STAT3. Functional prediction with bioinformatics programs of the Sorting Intolerant from Tolerant (SIFT) and the Polymorphism Phenotyping (PolyPhen) reported “deleterious (SIFT score 0.02)” and “probably damaging (PSIC score difference 2.94)” values, respectively. Further study of family members revealed that neither his parents, nor his twin brother carried the mutation, indicating the mutation was likely to occur de novo in our patient. Conclusion: The mutation,p.Y657S,in SH2 domain of STAT3 is a disease-causing mutation in the boy with HIES.

Keywords

Hyper-IgE syndrome Staphylococcal infection Liver abscess Pneumatocele The signal transducer and activator of transcription 3(STAT3) 

Notes

Acknowledgments

Qiang Li has received a research funding from the Department of Science and Technology of Sichuan Province, China (No.2008JY0029-1). We deeply thank Professor Yu-lung Lau*, Professor Wen-wei Tu* and Dr.Koon-wing Chan* for their invaluable help (Qiang Li has received a 3-months training in molecular diagnosis of primary immunodeficiency disease in the Department of Paediatrics & Adolescent Medicine, Hong Kong University). We are also grateful to the patient and his parents for their cooperation.

*Department of Paediatrics & Adolescent Medicine, Hong Kong University.

Conflict of Interest Statement

Qiang Li has received research support from the Department of Science and Technology of Sichuan Province, China (No.2008JY0029-1). All authors declare that no actual or potential conflict of interest in relation to this article exists.

References

  1. 1.
    Buckley RH, Wray BB, Belmaker EZ (1972) Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 49:59–70PubMedGoogle Scholar
  2. 2.
    Davis SD, Schaller J, Wedgwood RJ (1966) Job's syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet 1:1013–1015PubMedCrossRefGoogle Scholar
  3. 3.
    Engelhardt KR, McGhee S, Winkler S et al (2009) Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. Allergy Clin Immunol 124:1289–1302.e4CrossRefGoogle Scholar
  4. 4.
    Fanconi S, Seger RA, Willi U et al (1984) Oral chloramphenicol therapy for multiple liver abscesses in hyperimmunoglobulinemia E syndrome. Eur J Pediatr 142:292–295PubMedCrossRefGoogle Scholar
  5. 5.
    Grimbacher B, Schäffer AA, Holland SM et al (1999) Genetic linkage of hyper-IgE syndrome to chrosome 4. Am J Hum Genet 65:735–744PubMedCrossRefGoogle Scholar
  6. 6.
    Holland SM, DeLeo FR, Elloumi HZ et al (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357:1608–1619PubMedCrossRefGoogle Scholar
  7. 7.
    Jiao H, Tóth B, Erdos M et al (2008) Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups. Mol Immunol 46:202–206PubMedCrossRefGoogle Scholar
  8. 8.
    Milner JD, Brenchley JM, Laurence A et al (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773–776PubMedCrossRefGoogle Scholar
  9. 9.
    Minegishi Y, Karasuyama H (2007) Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency. Curr Opin Allergy Clin Immunol 7:506–509PubMedCrossRefGoogle Scholar
  10. 10.
    Minegishi Y, Saito M, Tsuchiya S et al (2007) Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448:1058–1062PubMedCrossRefGoogle Scholar
  11. 11.
    Minegishi Y (2009) Hyper-IgE syndrome. Curr Opin Immunol 21:487–492PubMedCrossRefGoogle Scholar
  12. 12.
    Minegishi Y, Saito M, Nagasawa M et al (2009) Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. J Exp Med 206:1291–1301PubMedCrossRefGoogle Scholar
  13. 13.
    Renner ED, Puck JM, Holland SM et al (2004) Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr 144:93–99PubMedCrossRefGoogle Scholar
  14. 14.
    Renner ED, Rylaarsdam S, Anover-Sombke S et al (2008) Novel signal transducer and activator of transcription 3(STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. J Allergy Clin Immunol 122(1):181–187PubMedCrossRefGoogle Scholar
  15. 15.
    Roy AD, Mcllrath EM, Mawhinney H (1982) Multiple liver abscesses in a patient with hyper IgE syndrome. J R Coll Surg Edinb 27:224–227PubMedGoogle Scholar
  16. 16.
    Sass V, Schneider T, Wilmes M et al (2010) Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci. Infect immune 78:2793–2800CrossRefGoogle Scholar
  17. 17.
    Tangye SG, Cook MC, Fulcher DA (2009) Insight into the role of STAT3 in human lymphocyte differentiation as revealed by the hyper-IgE syndrome. J Immunol 182:21–28PubMedGoogle Scholar
  18. 18.
    Winkelstein JA, Marino MC, Johnston RB Jr et al (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Med Baltim 79:155–169CrossRefGoogle Scholar
  19. 19.
    Woellner C, Gertz EM, Schäffer AA et al (2010) Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol 125:424–432.e8PubMedCrossRefGoogle Scholar
  20. 20.
    Xu X, Kasembeli MM, Jiang X et al (2009) Chemical probes that competitively and selectively inhibit STAT3 activation. PLoS ONE 4:e4783PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang Q, Davis JC, Lamborn IT et al (2009) Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 361:2046–2055PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jin-yan Liu
    • 1
  • Qiang Li
    • 1
  • Ting-ting Chen
    • 1
  • Xia Guo
    • 1
  • Jiao Ge
    • 1
  • Li-xing Yuan
    • 1
  1. 1.Department of Pediatric Hematology/ImmunologyWest China Second University Hospital, Sichuan UniversityChengduChina

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