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Clinical and Immunological Characterization of ICF Syndrome in Japan

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Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Objective

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive primary immunodeficiency. Hypogammaglobulinemia is a major manifestation of ICF syndrome, but immunoglobulin replacement therapy does not seem to be effective for some ICF patients. Therefore, we aimed to reassess the immunological characteristics of this syndrome.

Methods

Eleven Japanese patients with ICF syndrome were enrolled. We performed whole-exome sequencing in four cases and homozygosity mapping using SNP analysis in two. We evaluated their clinical manifestations and immunological status.

Results

We newly diagnosed six ICF patients who had tentatively been diagnosed with common variable immunodeficiency. We identified two novel mutations in the DNMT3B gene and one novel mutation in the ZBTB24 gene. All patients showed low serum IgG and/or IgG2 levels and were treated by periodic immunoglobulin replacement therapy. Three of the six patients showed worse results of the mitogen-induced lymphocyte proliferation test. Analyses of lymphocyte subpopulations revealed that CD19+CD27+ memory B cells were low in seven of nine patients, CD3+ T cells were low in three patients, CD4/8 ratio was inverted in five patients, CD31+ recent thymic emigrant cells were low in two patients, and CD19+ B cells were low in four patients compared with those in the normal controls. ICF2 patients showed lower proportions of CD19+ B cells and CD16+56+ NK cells and significantly higher proportions of CD3+ T cells than ICF1 patients. T cell receptor excision circles were undetectable in two patients. Despite being treated by immunoglobulin replacement therapy, three patients died of influenza virus, fatal viral infection with persistent Epstein–Barr virus infection, or JC virus infection. One of three dead patients showed normal intelligence with mild facial anomaly. Two patients presented with autoimmune or inflammatory manifestations. Infectious episodes decreased in three patients who were started on trimethoprim–sulfamethoxazole and/or antifungal drugs in addition to immunoglobulin replacement therapy. These patients might have suffered from T cell immunodeficiency.

Conclusion

These results indicate that patients with ICF syndrome have a phenotype of combined immunodeficiency. Thus, to achieve a better prognosis, these patients should be treated as having combined immunodeficiency in addition to receiving immunoglobulin replacement therapy.

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Abbreviations

CDCA7:

Cell division cycle-associated protein 7

Con A:

Concanavalin A

DNMT3B:

DNA methyltransferase 3B gene

HELLS:

Helicase, lymphoid-specific

HSCT:

Hematopoietic stem cell transplantation

ICF:

Immunodeficiency, centromeric instability, and facial anomalies

KREC:

Kappa-deleting recombination excision circles

NGS:

Next-generation sequencing

PCR:

Polymerase chain reaction

PHA:

Phytohemagglutinin

PML:

Progressive multifocal leukoencephalopathy

RTE:

Recent thymic emigrant cells

TREC:

T cell receptor excision circles

ZBTB24:

Zinc finger and BTB domain-containing 24 gene

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Acknowledgments

We thank Dr. Takehiro Takashima, Dr. Koichi Inagaki, Dr. Naomi Terada, Ms. Kaori Tomita, and Ms. Kimiko Gasa for their excellent technical assistance. We are grateful to the patients and their families for their participation in this study.

Authorship Contributions

C.K., K.I., H.K., and S.N. designed the study and wrote the manuscript. T.K., K.H., N.N., and T-W.Y. performed the flow cytometric analysis and collected the data. T.O., E.N., and O.O. performed the gene analysis. A.O., T.S., H.T., S.T., M.H., A.H., S.W., and T.S. cared for the patients. H.S., T.K., and T.M. contributed to the critical discussion.

Author information

Authors and Affiliations

  1. Department of Pediatrics, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-0042, Japan

    Chikako Kamae, Tamaki Kato, Kenichi Honma, Noriko Nakagawa & Shigeaki Nonoyama

  2. Department of Pediatrics, Self Defense Forces Central Hospital, Tokyo, Japan

    Chikako Kamae, Tamaki Kato & Noriko Nakagawa

  3. Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Kohsuke Imai

  4. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Tsubasa Okano, Tzu-Wen Yeh & Tomohiro Morio

  5. Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Emiko Noguchi

  6. Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan

    Akira Ohara

  7. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan

    Tomonari Shigemura

  8. Department of Neurology, National Hospital Organization, Tottori Medical Center, Tottori, Japan

    Hiroshi Takahashi

  9. Department of Infectious Diseases, Okinawa Chubu Hospital, Uruma, Japan

    Shunichi Takakura

  10. Department of Pediatrics, Uwajima City Hospital, Uwajima, Japan

    Masatoshi Hayashi

  11. Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan

    Aoi Honma & Seiichi Watanabe

  12. Department of Pediatrics, Nippon Medical School Tama Nagayama Hospital, Tama, Japan

    Tomoko Shigemori

  13. Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan

    Osamu Ohara

  14. Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Hiroyuki Sasaki

  15. Faculty of Child Studies, Seitoku University, Matsudo, Japan

    Takeo Kubota

  16. Department of Child Health and Development, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Hirokazu Kanegane

Authors
  1. Chikako Kamae
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  2. Kohsuke Imai
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  3. Tamaki Kato
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  4. Tsubasa Okano
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  5. Kenichi Honma
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  6. Noriko Nakagawa
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  7. Tzu-Wen Yeh
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  8. Emiko Noguchi
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  9. Akira Ohara
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  10. Tomonari Shigemura
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  11. Hiroshi Takahashi
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  12. Shunichi Takakura
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  13. Masatoshi Hayashi
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  14. Aoi Honma
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  15. Seiichi Watanabe
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  16. Tomoko Shigemori
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  17. Osamu Ohara
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  18. Hiroyuki Sasaki
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  19. Takeo Kubota
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  20. Tomohiro Morio
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  21. Hirokazu Kanegane
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  22. Shigeaki Nonoyama
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Corresponding author

Correspondence to Chikako Kamae.

Ethics declarations

Written informed consent was obtained from the parents of the pediatric patients and from the adult patients, in accordance with the Declaration of Helsinki. The study protocol was approved by the ethics board of the National Defense Medical College and Tokyo Medical and Dental University.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Electronic Supplementary Material

Figure S1

Immunoglobulin levels of ICF patients. Serum immunoglobulin levels of patients with ICF1 (white circle) and ICF2 (black circle) are shown. (A) Serum levels of IgG. (B) Serum levels of IgG2. (C) Serum levels of IgA. (D) Serum levels of IgM. Each immunoglobulin value is expressed separately for the ICF subtypes (ICF1 or ICF2) and each age group (7–12 months old, 3–5 years old, and adult). The horizontal bars in the figures show the average value of each age group. (PPTX 90 kb). The normal values of serum level globulins were taken from Stiehm et al. [16]. We defined normal ranges of serum levels of globulins as from 10th (or − 1.28 SD) to 90th (or + 1.28 SD) [16] as shown by vertical bars.

Figure S2

Lymphocyte subpopulations of patients with ICF syndrome. Lymphocyte subpopulations of patients with ICF1 (white circle) and ICF2 (black circle) are shown. (A) Percentages of CD3+ T cells. (B) The ratios of CD4+ to CD8+ T cell lymphocytes. (C) Percentages of CD31+ recent thymic emigrant cells (RTE) among CD3+CD4+CD45RA+ cells. (D) Percentages of CD19+ B cells. (E) Percentages of CD19+CD27+ memory B cells. (F) Percentages of CD16+56+ NK cells. Each lymphocyte subpopulation is expressed separately for the ICF subtypes (ICF1 or ICF2) and each age group (2–6 years old, 7–19 years old, and adult). The horizontal bars in the figures show the average value of each age group. The normal percentages of control data were taken from the work of Takashima et al. [18]. Vertical bars indicate the range from − 1.28 standard deviations (10th) to + 1.28 standard deviations (90th) of normal controls of each age group (PPTX 121 kb)

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Kamae, C., Imai, K., Kato, T. et al. Clinical and Immunological Characterization of ICF Syndrome in Japan. J Clin Immunol 38, 927–937 (2018). https://doi.org/10.1007/s10875-018-0559-y

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  • DOI: https://doi.org/10.1007/s10875-018-0559-y

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