Chikako Kamae1,2, Kohsuke Imai3, Tamaki Kato4,5, Tsubasa Okano6, Kenichi Honma4, Noriko Nakagawa4,5, Tzu-Wen Yeh6, Emiko Noguchi7, Akira Ohara8, Tomonari Shigemura9, Hiroshi Takahashi10, Shunichi Takakura11, Masatoshi Hayashi12, Aoi Honma13, Seiichi Watanabe13, Tomoko Shigemori14, Osamu Ohara15, Hiroyuki Sasaki16, Takeo Kubota17, Tomohiro Morio6, Hirokazu Kanegane18, Shigeaki Nonoyama4. 1. Department of Pediatrics, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-0042, Japan. shochikako310@gmail.com. 2. Department of Pediatrics, Self Defense Forces Central Hospital, Tokyo, Japan. shochikako310@gmail.com. 3. Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 4. Department of Pediatrics, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-0042, Japan. 5. Department of Pediatrics, Self Defense Forces Central Hospital, Tokyo, Japan. 6. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 7. Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 8. Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan. 9. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan. 10. Department of Neurology, National Hospital Organization, Tottori Medical Center, Tottori, Japan. 11. Department of Infectious Diseases, Okinawa Chubu Hospital, Uruma, Japan. 12. Department of Pediatrics, Uwajima City Hospital, Uwajima, Japan. 13. Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan. 14. Department of Pediatrics, Nippon Medical School Tama Nagayama Hospital, Tama, Japan. 15. Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan. 16. Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. 17. Faculty of Child Studies, Seitoku University, Matsudo, Japan. 18. Department of Child Health and Development, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
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.
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 ICFpatients. 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 ICFpatients 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. ICF2patients showed lower proportions of CD19+ B cells and CD16+56+ NK cells and significantly higher proportions of CD3+ T cells than ICF1patients. 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.
Entities:
Keywords:
B cell immunodeficiency; ICF syndrome; T cell immunodeficiency; TREC; combined immunodeficiency
Authors: A Pezzolo; I Prigione; P Facchetti; E Castellano; M Viale; G Gimelli; V Pistoia Journal: J Allergy Clin Immunol Date: 2001-08 Impact factor: 10.793
Authors: G L Xu; T H Bestor; D Bourc'his; C L Hsieh; N Tommerup; M Bugge; M Hulten; X Qu; J J Russo; E Viegas-Péquignot Journal: Nature Date: 1999-11-11 Impact factor: 49.962
Authors: R S Hansen; C Wijmenga; P Luo; A M Stanek; T K Canfield; C M Weemaes; S M Gartler Journal: Proc Natl Acad Sci U S A Date: 1999-12-07 Impact factor: 11.205
Authors: Corry M R Weemaes; Maarten J D van Tol; Jun Wang; Monique M van Ostaijen-ten Dam; Marja C J A van Eggermond; Peter E Thijssen; Caner Aytekin; Nicola Brunetti-Pierri; Mirjam van der Burg; E Graham Davies; Alina Ferster; Dieter Furthner; Giorgio Gimelli; Andy Gennery; Barbara Kloeckener-Gruissem; Stephan Meyn; Cynthia Powell; Ismail Reisli; Catharina Schuetz; Ansgar Schulz; Andrea Shugar; Peter J van den Elsen; Silvère M van der Maarel Journal: Eur J Hum Genet Date: 2013-03-13 Impact factor: 4.246
Authors: William T Shearer; Howard M Rosenblatt; Rebecca S Gelman; Rebecca Oyomopito; Susan Plaeger; E Richard Stiehm; Diane W Wara; Steven D Douglas; Katherine Luzuriaga; Elizabeth J McFarland; Ram Yogev; Mobeen H Rathore; Wende Levy; Bobbie L Graham; Stephen A Spector Journal: J Allergy Clin Immunol Date: 2003-11 Impact factor: 10.793
Authors: Peter E Thijssen; Yuya Ito; Giacomo Grillo; Jun Wang; Guillaume Velasco; Hirohisa Nitta; Motoko Unoki; Minako Yoshihara; Mikita Suyama; Yu Sun; Richard J L F Lemmers; Jessica C de Greef; Andrew Gennery; Paolo Picco; Barbara Kloeckener-Gruissem; Tayfun Güngör; Ismail Reisli; Capucine Picard; Kamila Kebaili; Bertrand Roquelaure; Tsuyako Iwai; Ikuko Kondo; Takeo Kubota; Monique M van Ostaijen-Ten Dam; Maarten J D van Tol; Corry Weemaes; Claire Francastel; Silvère M van der Maarel; Hiroyuki Sasaki Journal: Nat Commun Date: 2015-07-28 Impact factor: 14.919
Authors: Francesco Licciardi; Marlinde van den Boogaard; Marta Delle Piane; Pier Angelo Tovo; Davide Montin Journal: J Clin Immunol Date: 2019-02-04 Impact factor: 8.317
Authors: Chiara Parodi; Elisabetta Di Fede; Angela Peron; Ilaria Viganò; Paolo Grazioli; Silvia Castiglioni; Richard H Finnell; Cristina Gervasini; Aglaia Vignoli; Valentina Massa Journal: Front Cell Dev Biol Date: 2021-04-20
Authors: Monica T Kraft; Lubna S Mehyar; Benjamin T Prince; Shalini C Reshmi; Roshini S Abraham; Rolla Abu-Arja Journal: J Clin Immunol Date: 2021-02-05 Impact factor: 8.317