X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency disorder (PID) (1, 2). It was first described in 1952 by the American pediatrician Ogden Bruton, making it the first hereditary immunodeficiency identified in humans (3, 4). The disease is caused by mutations in the Bruton’s tyrosine kinase (BTK) gene located on the X chromosome (Xq22), leading to B-cell developmental arrest (5). This results in a significant reduction or absence of mature B cells and extremely low or undetectable levels of immunoglobulins (IgG, IgA, IgM) (6).

Affected individuals are typically male (females are usually carriers), and symptoms usually appear 6–12 months after birth, when maternal antibody protection wanes. Patients suffer from recurrent bacterial infections (e.g., otitis media, pneumonia, sinusitis), particularly from encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae) (7). Without timely treatment, complications such as chronic lung disease and sepsis may occur. Intravenous immunoglobulin (IVIG) replacement therapy and antibiotic prophylaxis are the mainstays of management. Advances in genetic diagnosis and early intervention have significantly improved patient outcomes, but lifelong monitoring is required.

In this study, we report a previously undocumented BTK mutation in an XLA patient who died from septic shock and multi-organ failure.

XLA is a primary immunodeficiency disorder characterized by impaired B-cell development, leading to antibody deficiency and recurrent infections (8). Patients often present with severe bacterial infections, particularly in the ears, nose, throat, and respiratory tract. A 2022 study of the USIDNET registry involving 231 XLA patients with known BTK mutations identified common pathogenic microorganisms as Haemophilus influenzae (10.4%), Staphylococcus aureus (10.4%), Streptococcus pneumoniae (7.8%), and Pseudomonas aeruginosa (6.1%) (9). In this case, the patient had a history of multiple severe pneumonias and was admitted with septic shock, ultimately succumbing to multi-organ failure due to Pseudomonas aeruginosa infection. A 2016 study reported that the average age of onset for XLA was 2.15 ± 2.16 years, with a median of 1 year. Among 135 patients (77.59%), symptoms appeared before the age of 3, and only one case presented at 13 years (10). The average age at diagnosis was 7.09 ± 3.98 years (range: 0.17–19 years), with 87 patients (50.58%) diagnosed within the first 6 years. However, only 5 patients (2.91%) were diagnosed before 1 year of age. This patient exhibited bronchiectasis at 13 but was not properly evaluated. Over the past two years, recurrent pneumonias also failed to prompt an XLA diagnosis. The cornerstone of XLA treatment is regular immunoglobulin replacement therapy to prevent infections (9, 11). Unfortunately, this patient was not diagnosed early or given standardized immunoglobulin therapy, leading to recurrent infections and rapid disease progression. Additionally, septic shock and multi-organ failure further complicated treatment, resulting in a poor prognosis.

Mutations in the BTK gene, are the primary cause of XLA (12). BTK consists of five domains: catalytic kinase (SH1), SH2, Src homology (SH3), Pleckstrin homology (PH), and Tec homology (TH), spanning 19 exons (13, 14). The BTKbase, an international database documenting disease-causing variants in BTK associated with XLA, currently contains information on 2,310 DNA variants from 2,291 individuals, including 1,025 unique variants (15). Mutations predominantly occur in the kinase domain (49.4%), with missense mutations accounting for 41.5% and insertions for 1.8% (https://structure.bmc.lu.se/idbase/BTKbase/). Due to the wide variety of BTK mutations, correlating specific mutations with disease severity remains challenging, and no objective standard for symptom severity exists (16, 17).

In this case, whole-exome sequencing revealed two previously unreported insertion mutations in exon 15 of the BTK gene(NM_000061.3 exon15:c.1561insG, NM_000061.3 exon15:c.1565insTAGAA), located within the catalytic kinase (SH1) domain. These mutations likely impair BTK kinase function, leading to symptom onset at 13 and death at 20 due to Pseudomonas aeruginosa-induced multi-organ failure. Genetic testing is now widely used in clinical practice, and early diagnosis combined with standardized treatment can prevent disease progression (18). Dana O’Toole’s research indicates that respiratory infections are a common cause of death in XLA patients. Screening for B-cell developmental defects in newborns provides an opportunity to prevent pulmonary infections through early diagnosis and treatment initiation. This approach helps increase clinical suspicion of XLA in patients with recurrent infections and assists healthcare providers in anticipating infection patterns in XLA patients (9). Although experimental approaches such as virus-mediated oligonucleotide gene therapy in mice and hematopoietic stem cell gene editing are under investigation, there is currently no cure for XLA in clinical practice (19, 20).

X-linked agammaglobulinemia is a life-threatening immunodeficiency. Early diagnosis and standardized immunoglobulin replacement therapy are critical. This case underscores the need for heightened clinical awareness of primary immunodeficiencies, particularly in patients with recurrent infections. Prompt immunological and genetic testing can improve outcomes. Therefore, we advocate for the inclusion of severe B-cell developmental defects (such as XLA) in newborn screening programs to prevent such fatal outcomes.