Journal of Clinical Immunology

, Volume 36, Issue 7, pp 641–648 | Cite as

Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1

  • Safa BarisEmail author
  • Fayhan Alroqi
  • Ayca Kiykim
  • Elif Karakoc-Aydiner
  • Ismail Ogulur
  • Ahmet Ozen
  • Louis-Marie Charbonnier
  • Mustafa Bakır
  • Kaan Boztug
  • Talal A. Chatila
  • Isil B. Barlan
Original Article



Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID).


Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17+ T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer.


Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4+ T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-β and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib.


STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.


STAT1 gain-of-function mutation mucocutaneous candidiasis combined immunodeficiency autoimmunity ruxolitinib 



This manuscript is dedicated to the memory of Professor Dr. Işıl Berat Barlan (1958–2015). This work was supported by the National Institutes of Health (5R01AI065617), to T.A.C.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Safa Baris
    • 1
    Email author
  • Fayhan Alroqi
    • 2
  • Ayca Kiykim
    • 1
  • Elif Karakoc-Aydiner
    • 1
  • Ismail Ogulur
    • 1
  • Ahmet Ozen
    • 1
  • Louis-Marie Charbonnier
    • 2
  • Mustafa Bakır
    • 1
  • Kaan Boztug
    • 3
  • Talal A. Chatila
    • 2
  • Isil B. Barlan
    • 1
  1. 1.Division of Pediatric Allergy/ImmunologyMarmara UniversityIstanbulTurkey
  2. 2.Division of Immunology, Boston Children’s Hospital and Department of PediatricsHarvard Medical SchoolBostonUSA
  3. 3.CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria

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