X-Linked Agammaglobulinemia
The diagnosis is X-linked agammaglobulinemia (XLA), option C. The combination of recurrent sinopulmonary infections, recurrent giardiasis, absent palpable lymph nodes, positive family history of sepsis death (suggesting X-linked inheritance), and male gender in a 4-year-old patient is pathognomonic for XLA. 1, 2
Key Diagnostic Features Present
The absence of palpable lymph nodes is the critical physical finding that distinguishes XLA from other immunodeficiencies. Patients with agammaglobulinemia characteristically lack lymphoid tissue due to absent or severely reduced B cells, presenting with absent tonsils and lymph nodes—a finding distinct from other forms of antibody deficiency and combined immunodeficiencies. 3, 2
The clinical presentation fits XLA precisely:
Recurrent sinopulmonary infections (6 episodes) with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae are the hallmark presentation, typically occurring in the first 2 years of life but can present up to age 5 or later. 3, 1
Recurrent giardiasis (>4 episodes) and gastroenteritis represent the gastrointestinal manifestations common in XLA, occurring in 35% of patients due to disturbed mucosal immunity. 4, 5
Family history of sepsis death strongly suggests X-linked inheritance pattern, with affected maternal male relatives being characteristic of XLA. 3, 2
Why Other Options Are Incorrect
Severe Combined Immunodeficiency (SCID) is excluded because these patients would not survive to age 4 with only bacterial infections—they would have opportunistic infections (Pneumocystis, fungal, viral) and failure to thrive much earlier, typically presenting in the first 6 months of life. 1 The pattern of bacterial infections without opportunistic infections supports agammaglobulinemia rather than SCID. 1
Common Variable Immunodeficiency (CVID) is unlikely because the diagnosis of CVID should only be considered in patients older than 4 years, and this patient is exactly 4 years old. 3 More importantly, CVID patients typically have palpable lymph nodes and tonsils, unlike XLA patients who characteristically lack these structures. 3
Confirmatory Testing Required
The diagnosis should be confirmed with:
Serum immunoglobulin levels: IgG usually <100 mg/dL, IgM <20 mg/dL, IgA <10 mg/dL. 3
Peripheral blood CD19+ B-cell count: <2% is characteristic and diagnostic. 3, 1
BTK gene mutation analysis: Approximately 85% of agammaglobulinemia cases are X-linked due to mutations in the Bruton tyrosine kinase (BTK) gene. 3, 2
Immediate Management Priorities
Do not delay treatment waiting for genetic confirmation—initiate therapy based on clinical presentation and immunoglobulin levels. 1
Initiate lifelong IgG replacement therapy immediately at 400-600 mg/kg every 3-4 weeks intravenously or weekly subcutaneously to prevent further infections and irreversible complications. 1, 2
Aggressive antimicrobial therapy for current infections with attention to encapsulated bacteria. 3, 2
Monitor for enteroviral CNS infections, particularly ECHO virus meningoencephalitis, which is a specific and potentially fatal complication of XLA. 3, 1
Careful pulmonary monitoring as chronic pulmonary disease with resultant cardiac failure is a major cause of death, and 5 of 6 patients in one series had already developed bronchiectasis by diagnosis. 4, 6
Critical Pitfall to Avoid
Do not confuse this with transient hypogammaglobulinemia of infancy, which would not present with undetectable levels of all three immunoglobulin classes, recurrent severe infections, and absent lymph nodes. 1 The severity and pattern of infections, combined with absent lymphoid tissue, makes XLA the definitive diagnosis.