Ref Number = ASPR0022
What PID to Suspect When a Child Presents With Difficult to Treat Mycobacterial Infections?
Hidenori Ohnishi
Department of Pediatrics, Graduate school of medicine, Gifu University, Gifu, Japan
*E-mail: ohnishih@gifu-u.ac.jp
Primary immunodeficiency syndrome was known as including the various kinds of diseases. In this disease group, some of diseases show the immunodeficiency against mycobacterial species. The representative diseases are T cell deficiency, especially severe combined immunodeficiency (SCID), Phagocytic defects including Chronic granulomatous disease (CGD) and Mendelian susceptibility to mycobacterial disease (MSMD) 1. Because, BCG vaccination is performed from 5 months old in Japan, it is important task to avoid this risky vaccination with the rapid diagnosis. T-cell Receptor Excision circles (TREC) as a new-born screening for SCID is starting to be introduced in various local area in Japan. However, it is difficult to do the new-born screening for CGD and MSMD. CGD can be diagnosed with the examination of the neutrophil sterilizing function and then the genetic analysis of NADPH oxidase components including CYBB is performed. It is one problem that because NCF1, which code p47phox has pseudogene, the genetic analysis is difficult. As one of the answers of this problem, the detection method of the protein expression of the components including p47phox with flowcytometry was established 2. Mendelian susceptibility to mycobacterial disease (MSMD) specifically show the immunodeficiency against mycobacterial species. Because almost of MSMD does not show any abnormality of the commercial based immunological tests, it is difficult to diagnose before onset. In the cohort study in Japan, partial IFNGR1 deficiency was high frequent and one NEMO (IKBKG) deficiency patient was identified 3. Although, the immunodeficiency normally occurs for only male with NEMO mutation but not female, we recently identified a rare case of female NEMO deficiency showed the mycobacterial infection 4. After that cohort study about MSMD in Japan, STAT1-loss of function (LOF) patients were also identified. Interestingly, to date, three types of abnormality of STAT1 gene is known; complete STAT1 deficiency, partial STAT1 deficiency and STAT1-gain of function (GOF). With the protein structure of STAT1, we may be able to predict the identified mutation whether it is LOF or GOF 5. In this presentation, my colleague?s experienced cases of these diseases which have the risk for infection of mycobacteria will be shown. 
Keywords: Chronic granulomatous disease (CGD); Mendelian susceptibility to mycobacterial disease (MSMD); Severe combined immunodeficiency (SCID)
Acknowledgement: The author thank the Health and Labour Science Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan. The clinical information of the cases of SCID, CGD, MSMD was kindly provided by Ryuhei Yasuoka of Hamamatsu University School of medicine, Emi Tannaka and Kunihiro Shinoda of Gifu Municipal Hospital, and Satoshi Okada of Hiroshima University.
1. Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S182-94.
2. Hoshina T, Takada H, Sasaki-Mihara Y, Kusuhara K, Ohshima K, Okada S, Kobayashi M, Ohara O, Hara T. Clinical and host genetic characteristics of Mendelian susceptibility to mycobacterial diseases in Japan. J Clin Immunol. 2011 Jun;31(3):309-14.
3. Wada T, Muraoka M, Toma T, Imai T, Shigemura T, Agematsu K, Haraguchi K, Moriuchi H, Oh-Ishi T, Kitoh T, Ohara O, Morio T, Yachie A. Rapid detection of intracellular p47phox and p67phox by flow cytometry; useful screening tests for chronic granulomatous disease. J Clin Immunol. 2013 May;33(4):857-64.
4. Ohnishi H, Kishimoto Y, Taguchi T, Kawamoto N, Nakama M, Kawai T, Nakayama M, Ohara O, Orii K, Fukao T. Immunodeficiency in Two Female Patients with Incontinentia Pigmenti with Heterozygous NEMO Mutation Diagnosed by LPS Unresponsiveness. J Clin Immunol. 2017 Aug;37(6):529-538.
5. Kagawa R, Fujiki R, Tsumura M, Sakata S, Nishimura S, Itan Y, Kong XF, Kato Z, Ohnishi H, Hirata O, Saito S, Ikeda M, El Baghdadi J, Bousfiha A, Fujiwara K, Oleastro M, Yancoski J, Perez L, Danielian S, Ailal F, Takada H, Hara T, Puel A, Boisson-Dupuis S, Bustamante J, Casanova JL, Ohara O, Okada S, Kobayashi M. Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants. J Allergy Clin Immunol. 2017 Jul;140(1):232-241.
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