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Autosomal-Dominant Chronic Mucocutaneous Candidiasis with STAT1-Mutation can be Complicated with Chronic Active Hepatitis and Hypothyroidism

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Abstract

Purpose

To describe a case of autosomal-dominant (AD)-chronic mucocutaneous candidiasis (CMC) with a signal transducer and activator of transcription (STAT) 1 gene mutation, and some of the important complications of this disease such as chronic hepatitis.

Methods

We present a 23-year-old woman with CMC, chronic active hepatitis, and hypothyroidism. Her father also had CMC. We performed several immunological analyses of blood and liver samples, and searched for gene mutations for CMC in the patient and her father.

Results

We identified the heterozygous substitution c.821 G > A (p.Arg274Gln) in the STAT1 gene of both the patient and her father. The level of β-glucan induced interferon (IFN)-γ in her blood cells was significantly low. Immunoblot analysis detected serum anti-interleukin (IL)-17 F autoantibody. She was found to have increased (low-titer) antibodies related to her hypothyroidism and hepatitis. Her serum IL-18 levels fluctuated with her AST and ALT levels. Liver biopsy revealed CD68-positive cell infiltration and IL-18 expression in the sinusoidal regions. These results suggest that the chronic active hepatitis in this patient may be exacerbated by the excessive IL-18 accumulation caused by recurrent mucocutaneous fungal infection, and decreased IFN-γ production.

Conclusions

AD-CMC is known to be caused by a gain-of-function mutation of the STAT1 gene. Chronic active hepatitis is a rare complication of AD-CMC, with currently unknown pathogenesis. It seems that the clinical phenotype in this patient is modified by autoimmune mechanisms and cytokine dysregulation. AD-CMC can be complicated by various immune disorders including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

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Abbreviations

AD:

Autosomal dominant

AIRE:

Autoimmune regulator

ANA:

Antinuclear antibody

APECED:

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

AR:

Autosomal recessive

ASMA:

Anti-smooth muscle antibody

CARD:

Caspase recruitment domain-containing protein

CMC:

Chronic mucocutaneous candidiasis

DOCK:

Dedicator of cytokinesis

GAF:

Interferon-γ activating factor

HIES:

Hyper-IgE syndrome

IFN:

Interferon

IL:

Interleukin

ISGF3:

Interferon-stimulated-γ factor 3

LKM-1:

Liver-kidney microsome 1

MSMD:

Mendelian susceptibility to mycobacterial disease

PBMCs:

Peripheral blood mononuclear cells

PHA:

Phytohemagglutinin

STAT:

Signal transducer and activator of transcription

TNF:

Tumor necrosis factor

TPOAb:

Anti-thyroid peroxidase antibody

TSBAb:

Thyroid stimulating hormone blocking antibody

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Acknowledgments

We thank Dr. K. Kubota, Dr. T. Yamamoto, and K. Kasahara for their advice and technical help. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan and by Health and Labour Science Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan. The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan

    Tomohiro Hori, Hidenori Ohnishi, Takahide Teramoto, Toshiyuki Fukao & Naomi Kondo

  2. Department of Pediatrics, Chuno Kosei Hospital, Gifu, Japan

    Kohji Tsubouchi

  3. Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan

    Takafumi Naiki

  4. Department of Pathology, Gifu University Hospital, Gifu, Japan

    Yoshinobu Hirose

  5. Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

    Osamu Ohara

  6. Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Japan

    Osamu Ohara

  7. Department of Dermatology, Graduate School of Medicine, Gifu University, Gifu, Japan

    Mariko Seishima

  8. Department of Clinical Research, Nagara Medical Center, Gifu, Japan

    Hideo Kaneko

Authors
  1. Tomohiro Hori
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  2. Hidenori Ohnishi
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  3. Takahide Teramoto
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  9. Hideo Kaneko
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  10. Toshiyuki Fukao
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  11. Naomi Kondo
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Correspondence to Hidenori Ohnishi.

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Hori, T., Ohnishi, H., Teramoto, T. et al. Autosomal-Dominant Chronic Mucocutaneous Candidiasis with STAT1-Mutation can be Complicated with Chronic Active Hepatitis and Hypothyroidism. J Clin Immunol 32, 1213–1220 (2012). https://doi.org/10.1007/s10875-012-9744-6

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  • DOI: https://doi.org/10.1007/s10875-012-9744-6

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