What is the most likely diagnosis for a male child with a history of recurrent respiratory infections, gastroenteritis with giardiasis, greasy foul-smelling stool, and small tonsils, whose younger brother died of a similar disease?

X-Linked Agammaglobulinemia (XLA)

The most likely diagnosis is X-linked agammaglobulinemia (XLA), given the combination of recurrent respiratory infections, gastrointestinal infections with giardiasis, greasy foul-smelling stool indicating malabsorption, characteristically small/absent tonsils, and a family history of a male sibling dying from similar disease. 1

Key Diagnostic Features Supporting XLA

Clinical Presentation Pattern

• Recurrent respiratory infections (5-6 episodes) are the hallmark of XLA, occurring in 88% of patients, with upper respiratory tract involvement in 75% and lower respiratory tract in 65% 1
• Gastrointestinal infections with giardiasis (3-4 episodes) occur in 35% of XLA patients, often presenting with chronic diarrhea and malabsorption causing greasy, foul-smelling stool 1
• The greasy stool indicates fat malabsorption from chronic gastrointestinal infection, which is characteristic of antibody deficiency disorders like XLA 1

Pathognomonic Physical Finding

• Small or absent tonsils are pathognomonic for XLA, distinguishing it from other antibody deficiencies where lymphoid tissue is typically present 1
• This finding reflects the absence of B cells and lymphoid tissue development that characterizes XLA 1

Family History

• A younger brother dying of similar disease strongly suggests X-linked inheritance, which is seen in XLA affecting maternal male relatives 1
• Approximately 85% of agammaglobulinemia cases are X-linked (XLA) due to mutations in the BTK gene 1

Why Other Diagnoses Are Less Likely

Severe Combined Immunodeficiency (SCID) - Option B

• SCID presents with opportunistic infections (Pneumocystis, fungal, viral), not just bacterial respiratory and gastrointestinal infections 1
• SCID typically manifests within the first 3-6 months of life with failure to thrive, chronic diarrhea, and life-threatening infections 1
• The pattern of bacterial infections without opportunistic infections supports agammaglobulinemia rather than SCID 1
• This patient's presentation lacks the severe opportunistic infections and early life-threatening course typical of SCID 2

IgA Deficiency - Option C

• IgA deficiency is the mildest antibody deficiency and would not explain the severity of infections described 1
• Patients with isolated IgA deficiency typically have normal or near-normal IgG and IgM levels and less severe clinical manifestations 1
• The combination of severe respiratory infections, giardiasis with malabsorption, and absent tonsils far exceeds what would be expected with isolated IgA deficiency 3

Hyper IgE Syndrome - Option D

• Hyper IgE syndrome presents with eczema, recurrent staphylococcal skin abscesses, and pneumatoceles, not primarily respiratory and GI infections 1
• The clinical presentation described lacks the characteristic dermatologic findings (eczema, skin abscesses) and pulmonary complications (pneumatoceles) of Hyper IgE syndrome 4
• Joint involvement, lymphadenopathy, and skin lesions during febrile attacks would be expected in Hyper IgE syndrome but are not described in this case 4

Immediate Diagnostic Confirmation

Laboratory Tests to Order

• Serum immunoglobulin levels (IgG, IgA, IgM) - expect very low or undetectable levels 1
• Flow cytometry for CD19+ B cells - expect <2% of lymphocytes, which is characteristic of XLA 1
• T-cell enumeration - expect normal numbers and function, distinguishing XLA from combined immunodeficiencies 1
• The combination of undetectable IgG, IgM, and IgA levels with normal T-cell counts in an infant with recurrent bacterial infections is diagnostic of agammaglobulinemia 1

Critical Management Priorities

Immediate Interventions

• Initiate treatment immediately upon diagnosis without waiting for genetic confirmation, including intravenous immunoglobulin (IVIG) replacement therapy and aggressive antimicrobial therapy for current infections 1
• Do not delay diagnosis waiting for B-cell enumeration if immunoglobulin levels are in the agammaglobulinemic range—the clinical picture is sufficient to initiate treatment 1
• Agammaglobulinemia should be managed aggressively with antimicrobials, IgG replacement, and careful attention to pulmonary status 1

Long-Term Monitoring

• Monitor pulmonary status carefully to prevent bronchiectasis, which develops in 10-20% of patients despite treatment 1
• Watch for CNS enteroviral (ECHO virus) infections, which are specific complications of XLA 1
• Monitor for enteroviral infections, particularly CNS ECHO virus infections, which are specific complications of agammaglobulinemia 1

Common Pitfalls to Avoid

• Do not confuse with transient hypogammaglobulinemia of infancy, which would not present with undetectable levels of all three immunoglobulin classes 1
• Diagnosis of XLA may be delayed in some patients who have detectable (~2%) B cells in peripheral blood and significant levels of serum immunoglobulins, though they still present with severe and recurrent bacterial infections 5
• Significant levels of serum immunoglobulins in XLA patients do not necessarily mean less severe phenotype 5
• Earlier diagnosis and treatment initiation are associated with reduced lower respiratory tract infections and mortality; for every year increase in age at start of therapy, the odds of experiencing a lower respiratory tract infection increase by 21.6% 6