{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:52:57Z","timestamp":1791175977797,"version":"4.1.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Trisomy 21 is associated with combined immune dysregulation, including lymphopenia, impaired responses to vaccines, and heightened susceptibility to respiratory infections, driven in part by triplication of chromosome 21-encoded interferon receptor genes.\n                      <jats:italic>BACH2<\/jats:italic>\n                      haploinsufficiency is a rare monogenic immunodeficiency characterized by lymphopenia, hypogammaglobulinemia, and susceptibility to infections and autoimmune diseases. Co-occurrence of these two conditions has not been previously described.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      We report a 5-year longitudinal course in a Kenyan girl with trisomy 21, congenital heart disease, aspiration, and severe gastroesophageal reflux disease (GERD) found via whole exome sequencing to carry a heterozygous\n                      <jats:italic>BACH2<\/jats:italic>\n                      missense variant (c.1420C\u2009&amp;gt;\u2009G;p.Leu474Val) of uncertain significance; parental segregation remains incomplete. In silico protein structural modeling (FoldX and Missense3D) yielded discordant predictions of the variant's effect on the protein\u2019s stability and structure. Additional\n                      <jats:italic>in silico<\/jats:italic>\n                      pathogenicity predictions were also inconsistent: Sorting Intolerant from Tolerant (SIFT), Evolutionary Model of Variant Effect (EVE), PolyPhen-2, and CADD Phred scores predicted pathogenicity, while REVEL and AlphaMissense suggested a lack of deleteriousness. Persistent panlymphopenia and profoundly low IgM levels were documented throughout the follow-up period. Over these 5 years, the girl sustained six hospitalized lower respiratory tract infections (LRTIs), with four requiring intensive care, which were disseminated Bacille Calmette-Gu\u00e9rin (BCG) disease, respiratory syncytial virus and SARS-CoV-2 infections, and influenza A(H1N1)pdm09 pneumonia. Chest computed tomography at 4 years showed bilateral consolidations without bronchiectasis. Annual autoimmune screening remained negative.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This case illustrates the burden caused by severe and diverse respiratory pathogenic infections in a child with trisomy 21 and a candidate\n                      <jats:italic>BACH2<\/jats:italic>\n                      variant. Trisomy 21 alone plausibly explains much of the phenotype; an independent contribution from the\n                      <jats:italic>BACH2<\/jats:italic>\n                      variant remains unproven pending functional and segregation studies. Clinical considerations supported by this case include the potential value of prevaccination immunological screening to prevent BCG disease, equitable access to viral prophylaxis, and early specialist engagement in refractory cases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1934925","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:31:25Z","timestamp":1791174685000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Disseminated BCG disease and recurrent pulmonary infections in a child with trisomy 21 carrying a novel BACH2 variant of uncertain significance: a 5-year case report"],"prefix":"10.3389","volume":"13","author":[{"given":"Diana","family":"Marangu-Boore","sequence":"first","affiliation":[{"name":"Pediatric Pulmonology Division, Department of Pediatrics and Child Health, University of Nairobi","place":["Nairobi, Kenya"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Maugo","sequence":"additional","affiliation":[{"name":"Neonatology Division, Department of Pediatrics and Child Health, University of Nairobi","place":["Nairobi, Kenya"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita Afriye","family":"Boateng","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research","place":["Accra, Ghana"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e16220","DOI":"10.7554\/eLife.16220","article-title":"Trisomy 21 consistently activates the interferon response","volume":"5","author":"Sullivan","year":"2016","journal-title":"Elife"},{"key":"B2","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s10875-020-00803-9","article-title":"Three copies of four interferon receptor genes underlie a mild type I interferonopathy in down syndrome","volume":"40","author":"Kong","year":"2020","journal-title":"J Clin Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41588-023-01399-7","article-title":"Triplication of the interferon receptor locus contributes to hallmarks of down syndrome in a mouse model","volume":"55","author":"Waugh","year":"2023","journal-title":"Nat Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"621440","DOI":"10.3389\/fimmu.2021.621440","article-title":"Immune dysregulation and the increased risk of complications and mortality following respiratory tract infections in adults with down syndrome","volume":"12","author":"Illouz","year":"2021","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/s41586-023-05736-y","article-title":"Autoimmunity in Down's Syndrome via cytokines, CD4\u2005T cells and CD11c(+) B cells","volume":"615","author":"Malle","year":"2023","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1836558","DOI":"10.3389\/fimmu.2026.1836558","article-title":"Revisiting down syndrome through the lens of interferonopathy and innate immune dysregulation","volume":"17","author":"Wang","year":"2026","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"020413","DOI":"10.7189\/jogh.07.020413","article-title":"The burden of respiratory syncytial virus (RSV) associated acute lower respiratory infections in children with down syndrome: a systematic review and meta-analysis","volume":"7","author":"Chan","year":"2017","journal-title":"J Glob Health"},{"key":"B8","doi-asserted-by":"publisher","first-page":"246","DOI":"10.3390\/children11020246","article-title":"Recurrent respiratory infections in children with down syndrome: a review","volume":"11","author":"Ghezzi","year":"2024","journal-title":"Children (Basel)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1038\/nature12199","article-title":"BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis","volume":"498","author":"Roychoudhuri","year":"2013","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/nature02596","article-title":"The transcriptional programme of antibody class switching involves the repressor BACH2","volume":"429","author":"Muto","year":"2004","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/s41467-019-14112-2","article-title":"Attenuation of TCR-induced transcription by BACH2 controls regulatory T cell differentiation and homeostasis","volume":"11","author":"Sidwell","year":"2020","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/ni.3753","article-title":"BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency","volume":"18","author":"Afzali","year":"2017","journal-title":"Nat Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1007\/s10875-023-01506-7","article-title":"An early-onset SLE patient with a novel paternal inherited BACH2 mutation","volume":"43","author":"Zhou","year":"2023","journal-title":"J Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/j.jaci.2003.07.003","article-title":"Lymphocyte subsets in healthy children from birth through 18 years of age: the pediatric AIDS clinical trials group P1009 study","volume":"112","author":"Shearer","year":"2003","journal-title":"J Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.4049\/jimmunol.2100491","article-title":"CRISPR\/Cas9-mediated insertion of HIV long terminal repeat within BACH2 promotes expansion of T regulatory-like cells","volume":"208","author":"Christian","year":"2022","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/s12016-016-8538-7","article-title":"The Bach family of transcription factors: a comprehensive review","volume":"50","author":"Zhou","year":"2016","journal-title":"Clin Rev Allergy Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"891","DOI":"10.3390\/cells13110891","article-title":"BACH2. The future of induced T-regulatory cell therapies","volume":"13","author":"Zwick","year":"2024","journal-title":"Cells"},{"key":"B18","doi-asserted-by":"publisher","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/s41586-021-04043-8","article-title":"Disease variant prediction with deep generative models of evolutionary data","volume":"599","author":"Frazer","year":"2021","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"Unit7.20","DOI":"10.1002\/0471142905.hg0720s76","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","author":"Adzhubei","year":"2013","journal-title":"Curr Protoc Hum Genet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"248","DOI":"10.5114\/ceji.2018.80042","article-title":"Lymphocyte subgroups and recurrent infections in children with down syndrome\u2014a prospective case control study","volume":"43","author":"Mitwalli","year":"2018","journal-title":"Cent Eur J Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"105284","DOI":"10.1016\/j.exphem.2025.105284","article-title":"Feedback loops in B-cell chromatin regulation as a therapeutic target for modulating antibody production and malignancies: insights from BACH2","volume":"153","author":"Ochiai","year":"2026","journal-title":"Exp Hematol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3408","DOI":"10.1016\/j.vaccine.2018.03.009","article-title":"BCG vaccine: WHO position paper, February 2018\u2014recommendations.","volume":"36","year":"2018","journal-title":"Vaccine"},{"key":"B24","first-page":"1376","article-title":"Consensus statement on the revised World Health Organization recommendations for BCG vaccination in HIV-infected infants","volume":"12","author":"Hesseling","year":"2008","journal-title":"Int J Tuberc Lung Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"ofaf132","DOI":"10.1093\/ofid\/ofaf132","article-title":"Limitations of the MTB\/RIF assay: an xpert review of 4 clinical cases","volume":"12","author":"Haas","year":"2025","journal-title":"Open Forum Infect Dis"},{"key":"B26","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s10875-020-00758-x","article-title":"Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification","volume":"40","author":"Bousfiha","year":"2020","journal-title":"J Clin Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1056\/NEJMoa2110275","article-title":"Nirsevimab for prevention of RSV in healthy late-preterm and term infants","volume":"386","author":"Hammitt","year":"2022","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"461","DOI":"10.3389\/fped.2019.00461","article-title":"Allogeneic hematopoietic stem cell transplantation for congenital immune dysregulatory disorders","volume":"7","author":"Bakhtiar","year":"2019","journal-title":"Front Pediatr"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1934925\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:31:43Z","timestamp":1791174703000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1934925\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":28,"alternative-id":["10.3389\/fmed.2026.1934925"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1934925","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]},"article-number":"1934925"}}