Immune and Genetic Insights into Kabuki Syndrome: A Case Series

Introduction Kabuki syndrome is a rare disorder primarily associated with mutations in the KMT2D (autosomal dominant) and KDM6A (X-linked) genes. While these mutations may be linked to immune dysregulation, including humoral immunodeficiencies resembling common variable immunodeficiency with recurrent infections and impaired B cell memory differentiation [1], these associations are not well established. This study aims to further characterize immune dysregulation, clinical manifestations, and genetic variability in Kabuki syndrome to address this gap. Method This case series involves patients diagnosed with Kabuki syndrome at the University of Miami, following Institutional Review Board approval (Study #20240903). Electronic medical records were reviewed to analyze demographics, history of infections, autoimmunity, and relevant laboratory data. Findings The study included seven patients (4 males and 3 females), aged 14 months to 26 years (mean: 11.7 years, median: 5 years). Hypogammaglobulinemia was observed in 6/7 patients (86%), with low IgG in 4/7 (57%), low IgA in 2/7 (29%), and low IgM in 3/7 (43%). Lymphopenia was identified in 3/7 patients (43%) for CD3, 3/7 (43%) for CD4, and in 2/7 (29%) for CD8. 1/7 patients (14%) showed significant B cell subset abnormalities. Pathogenic or likely pathogenic KMT2D mutations were detected in 6/7 patients (86%), while 2/7 (29%) had variants of uncertain significance (CEP250, SALL1, and SRCAP). A duplication at 2q22.1 was noted in 1/7 patients (14%) without a clear clinical phenotype. Recurrent infections occurred in 3/7 patients (43%), mainly involving upper respiratory infections, otitis media, and pneumonia. Autoimmunity was reported in 1/7 patients (14%) and lymphoproliferative disorders in 2/7 (29%). Intravenous immunoglobulin therapy was administered to 3/7 patients (43%) and 1/7 (14%) received prophylactic vaccines for low pneumococcal antibody titers. Discussion This study finds that patients with Kabuki syndrome exhibit significant immune dysregulation, including hypogammaglobulinemia, lymphopenia, and recurrent infections, which are linked to genetic variability such as pathogenic KMT2D mutations and variants of uncertain significance. These findings support the need for routine immune evaluations, genetic testing, and targeted therapies, including immunoglobulin replacement and additional vaccinations, to guide personalized management and improve patient outcomes.