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

BackgroundTrisomy 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. BACH2 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.Case presentationWe 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 BACH2 missense variant (c.1420C > G;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’s stability and structure. Additional in silico 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-Guérin (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.ConclusionThis case illustrates the burden caused by severe and diverse respiratory pathogenic infections in a child with trisomy 21 and a candidate BACH2 variant. Trisomy 21 alone plausibly explains much of the phenotype; an independent contribution from the BACH2 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.