X-linked Agammaglobulinemia (XLA)
The most likely diagnosis is X-linked agammaglobulinemia (XLA), given the combination of recurrent sinopulmonary infections, giardiasis, failure to thrive, absent lymphadenopathy, and family history of death from infections. 1, 2
Key Diagnostic Features Supporting XLA
The absence of lymphadenopathy is the critical distinguishing feature that points away from SCID and toward agammaglobulinemia. 1 Patients with agammaglobulinemia characteristically lack lymphoid tissue due to absent or severely reduced B cells, while SCID patients typically present with infections so severe they often die before developing significant lymphadenopathy. 1
Clinical Presentation Pattern
- Recurrent sinopulmonary infections with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) are the hallmark of antibody deficiency disorders like XLA 1
- Giardiasis and recurrent gastroenteritis occur commonly in antibody deficiency states, as IgA and IgG are critical for mucosal immunity 1, 3
- Failure to thrive (weight and height below 3rd percentile) occurs in XLA due to chronic infections and malabsorption from gastrointestinal infections 1, 2
- Family history of death from infections suggests X-linked inheritance pattern, consistent with XLA 1, 2
Why Not SCID?
SCID can be excluded based on several key features:
- SCID presents much earlier (typically within first 3-6 months of life) with severe, disseminated, and opportunistic infections (PCP, CMV, disseminated BCG, fungal infections) 1, 4, 5
- SCID patients have profound failure to thrive with chronic diarrhea as a dominant feature from birth 1, 6, 7
- The pattern of only bacterial sinopulmonary infections and giardiasis without opportunistic infections is inconsistent with SCID 1
- SCID is uniformly fatal without treatment by age 1-2 years, whereas XLA patients can survive longer with recurrent but treatable bacterial infections 6, 7
Why Not Omenn Syndrome?
Omenn syndrome is excluded because:
- Omenn syndrome presents with erythroderma, hepatosplenomegaly, lymphadenopathy, and eosinophilia in early infancy 1
- The absence of lymphadenopathy in this patient is incompatible with Omenn syndrome 1
- Omenn syndrome is a variant of SCID with oligoclonal T-cell expansion causing inflammatory manifestations not described here 1
Expected Laboratory Findings in XLA
- Very low or undetectable IgG, IgA, and IgM levels (all three immunoglobulin classes) 1, 2
- CD19+ B cells <2% of lymphocytes (virtually absent B cells) 2
- Normal T-cell numbers and function (normal CD3+, CD4+, CD8+ counts and proliferation to mitogens) 1, 2
- Normal or elevated neutrophil counts (unless overwhelming sepsis) 1
Immediate Management Priorities
Initiate lifelong IgG replacement therapy immediately (400-600 mg/kg every 3-4 weeks intravenously or weekly subcutaneously) to prevent further infections and complications. 1, 2
- Aggressive antimicrobial therapy for current infections with extended courses as needed 1, 2
- Antibiotic prophylaxis may be needed for breakthrough infections despite adequate IgG replacement 1
- Monitor for enteroviral CNS infections (ECHO virus meningitis/encephalitis), which are specific life-threatening complications of XLA 1, 2
- Screen for Helicobacter species causing ecthyma or silent bacteremia, which is characteristic of agammaglobulinemia 1
Critical Pitfall to Avoid
Do not delay treatment waiting for genetic confirmation of BTK mutation—the clinical picture of undetectable immunoglobulins with absent B cells and normal T cells is sufficient to diagnose agammaglobulinemia and initiate IgG replacement. 2 Approximately 85% of cases are X-linked (BTK gene), with the remainder being autosomal recessive forms. 2