Bruton’s Agammaglobulinemia: Case Series and Literature Review From King Fahad Central Hospital, Jizan, Saudi Arabia

Introduction

X-linked agammaglobulinemia (XLA), also known as Bruton’s agammaglobulinemia, is a primary immunodeficiency affecting the humoral immune response, first described by Bruton in 1952 [1]. The disorder results from mutations in the Bruton tyrosine kinase (BTK) gene, located on the Xq22 region of the X chromosome, which is essential for normal B-cell development [1,2]. Mutations in the BTK gene disrupt B-cell maturation, resulting in substantially reduced levels of mature B lymphocytes, plasma cells, and various immunoglobulin (Ig) isotypes [3]. Consequently, patients with XLA are highly susceptible to recurrent infections, particularly respiratory infections caused by encapsulated bacteria, and gastrointestinal infections due to pathogens such as Salmonella and Giardia [4]. The cornerstone of XLA management is immunoglobulin replacement therapy, administered either intravenously (IVIG) or subcutaneously [5].

The prevalence of XLA varies by region, with approximately 250 cases per 100,000 men reported in Saudi Arabia and around 1 case per 190,000 men in the United States [6,7]. Diagnosis typically involves measuring serum immunoglobulin concentrations, enumerating B cells, and performing genetic testing to identify BTK mutations. More than 600 pathogenic variants of the BTK gene have been documented, and no single variant is predominant [8–11]. These genetic differences contribute to the heterogeneity of XLA, which may manifest with atypical features, including both IgE-mediated and non-IgE-mediated allergic reactions [12–14]. Given the high consanguinity rates in Saudi Arabia – ranging from 44% to 67% nationally and reaching 66.7% in the Jazan region – the likelihood of inherited immunodeficiency syndromes such as XLA is elevated in this population [15].

This case series and literature review aim to describe the clinical and genetic characteristics of XLA observed at King Fahad Central Hospital in Jizan, Saudi Arabia, thereby contributing valuable data to the global understanding of this rare and serious immunodeficiency disorder.

Case Reports

CASE 1:

A 14-month-old male child had a history of recurrent chest infections and significant developmental delay; eventually, he was diagnosed with agammaglobulinemia via whole-exome sequencing. The analysis identified a hemizygous pathogenic BTK variant (c.953_956del; p.S318Cfs*12) resulting in a frameshift and premature protein truncation, thus confirming the diagnosis of XLA. The patient had been born at home through an uncomplicated vaginal delivery without prenatal care. His early development was normal until approximately 5 months of age, when he began to exhibit developmental regression and frequent respiratory infections, leading to multiple hospital admissions.

By 14 months of age, his condition had worsened. He was referred to a peripheral hospital after 6 days of fever, cough, and diarrhea. Despite treatment with antibiotics and antiviral agents, including oseltamivir, cefotaxime, and vancomycin, his clinical condition remained unstable. Eventually, he was hospitalized more than 5 times for respiratory infections, raising suspicion of agammaglobulinemia due to the infection frequency and severity.

Physical examination revealed edema of the lower limbs, hands, and periorbital regions, along with coarse facial features. His abdomen was distended; he exhibited cutaneous lesions and reduced air entry in the lower left lung. Laboratory investigations demonstrated severe immunodeficiency, with greatly decreased levels of all immunoglobulin classes: IgM levels ranged from 0.03 to 0.15 g/L (reference: 0.4–2.3 g/L), IgG levels from 0.03 to 13.55 g/L (reference: 7–16 g/L), and IgA levels from 0 to 0.08 g/L (reference: 0.7–4 g/L). Complete blood count results showed clinically significant abnormalities, including white blood cell counts fluctuating from 2.14 × 10⁹/L to 18.64×10⁹/L (reference: 4.5–10×10⁹/L), persistently low hemoglobin levels around 6.3 g/dL (reference: 13–18 g/dL), and platelet counts varying from 12 to 563×10⁹/L (reference: 150–400×10⁹/L). He also had recurrent episodes of severe neutropenia, with neutrophil counts as low as 0.3×10⁹/L (reference: 2.5–7.5×10⁹/L), and elevated lymphocyte counts up to 13.69×10⁹/L (reference: 1.5–3.5×10⁹/L), further increasing his susceptibility to infections.

Imaging studies, including a computed tomography (CT) scan of the brain, revealed a subdural hygroma and mild cerebral atrophy (Figure 1). As the child grew older, adherence to the recommended monthly IVIG treatments declined, worsening his condition. At 2 years of age, he was admitted to the hospital with severe respiratory distress after missing 3 consecutive months of IVIG therapy due to social difficulties. He presented with fever, shortness of breath, and a worsening cough.

On examination, the patient was tachypneic (130 breaths/min), in respiratory distress, and exhibiting a distended abdomen with non-pitting edema of the lower limbs. Chest auscultation revealed bilateral wheezing and crackles. Despite aggressive management, including high-flow nasal cannula oxygen therapy, IVIG administration, and broad-spectrum antibiotics such as meropenem and vancomycin, his condition continued to deteriorate.

Throughout his illness, the patient experienced recurrent episodes of severe respiratory distress, frequently warranting intensive care. He was treated for multiple infections, including pneumonia, and required management of complications related to his immunodeficiency. Despite repeated interventions and the administration of IVIG, his prognosis remained poor. His clinical course was further complicated by inconsistent adherence to therapy, resulting in recurrent infections and repeated hospitalizations. Ultimately, the patient succumbed to his illness, primarily due to severe and recurrent respiratory infections associated with XLA and irregular treatment adherence.

The patient’s parents provided informed consent, verbally agreeing that the patient’s data could be used for this publication.

CASE 2:

A 3-year-old male child experienced repeated respiratory infections and severe neutropenia, leading to an eventual diagnosis of XLA. His history of repeated chest infections began at approximately 5 months of age, raising early suspicion of an underlying immunodeficiency. His first hospitalization was prompted by symptoms of gastroenteritis, including diarrhea and decreased oral intake, accompanied by severe neutropenia. Although he remained hydrated and alert, imaging studies (including CT scans) revealed bilateral pulmonary infiltrates with areas of consolidation (Figure 2) and ground-glass opacities consistent with pneumonia (Figure 3).

The diagnosis of agammaglobulinemia was confirmed through whole-exome sequencing, which identified a hemizygous BTK variant (c.1873del; p.Tyr625Thrfs*58) causing a frameshift and premature protein truncation. This genetic finding supported the diagnosis of XLA; it was consistent with the patient’s clinical presentation of recurrent infections and greatly reduced immunoglobulin levels. Laboratory investigations showed profoundly low immunoglobulin levels: IgG was 3.29 g/L (reference: 7–16 g/L), IgM ranged from 0.124 to 0.25 g/L (reference: 0.4–2.3 g/L), and IgA was undetectable at 0 g/L (reference: 0.7–4 g/L). Total IgE was within normal limits at 49.8 IU/mL (reference: <60 IU/mL). His complete blood count consistently revealed severe neutropenia involving neutrophil counts as low as 0, clinically significant anemia with hemoglobin levels decreasing to 8.8 g/dL (reference: 13–18 g/dL), and thrombocytosis, with platelet counts reaching 759×10⁹/L (reference: 150–400×10⁹/L). These findings reflected his heightened susceptibility to infections and the persistent challenges of disease management.

Throughout his clinical course, the patient experienced multiple severe infections, including nosocomial sepsis and urinary tract infections, requiring frequent hospitalizations and intensive treatment with broad-spectrum antibiotics such as vancomycin and tazocin. Despite regular IVIG therapy, difficulties in maintaining consistent adherence – particularly concerning timely IVIG administration – led to intervals of increased vulnerability to infection.

As the patient grew older, his condition stabilized to some extent with consistent IVIG therapy, although he continued to experience occasional respiratory infections. By the age of 4 years and 8 months, he was generally stable during follow-up visits, reporting no new complaints and exhibiting stable vital signs. Chest examinations remained clear, and he was active and afebrile. However, his clinical course was often disrupted by episodes of decreased appetite and activity, typically coinciding with acute infections. Despite these challenges, his management plan – which included regular IVIG therapy and close monitoring for infections – helped reduce the frequency and severity of his symptoms.

Although the patient’s outlook remained cautiously optimistic, the chronic nature of his condition and the recurrent infections requiring ongoing medical intervention complicated his clinical course. His experience underscored the importance of strict adherence to treatment regimens and continuous monitoring to prevent severe complications associated with XLA.

The patient’s parents provided informed consent, verbally agreeing that his data could be included in this publication.

Discussion

LIMITATIONS:

This case series is limited by its single-center design, which may restrict the generalizability of its findings. The small sample size of 2 cases also limits the ability to draw broader conclusions about XLA. Future studies with larger, multicenter cohorts and prospective designs are warranted to better assess long-term outcomes and optimize treatment strategies, particularly in regions with high consanguinity rates.

Conclusions

XLA presents substantial clinical challenges, primarily due to its association with recurrent severe infections. The cases described in this report highlight the critical roles of early diagnosis, consistent immunoglobulin replacement therapy, and close clinical monitoring in effective disease management. The differing outcomes observed underscore the importance of treatment adherence in preventing severe complications and improving long-term prognosis. Moreover, the identification of BTK gene mutations is essential for confirming the diagnosis and guiding family counseling, especially in regions with high consanguinity rates, such as Saudi Arabia. Ultimately, these findings highlight the need for continuous patient education and strict adherence to treatment protocols to optimize outcomes for patients with XLA.