A patient with recurrent respiratory and gastrointestinal infections, greasy foul-smelling stool, small tonsils, and a family history of a similar disease, what is the most likely diagnosis?

X-linked Agammaglobulinemia (XLA)

The most likely diagnosis is A - X-linked agammaglobulinemia (XLA), based on the constellation of recurrent respiratory and gastrointestinal infections with giardiasis, greasy foul-smelling stool (malabsorption), small tonsils on examination, and a family history suggesting X-linked inheritance. 1, 2

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, 3
• 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, 3
• The greasy stool indicates fat malabsorption from chronic gastrointestinal infection, which is characteristic of antibody deficiency disorders like XLA 1

Physical Examination Findings

• Small or absent tonsils are pathognomonic for XLA, distinguishing it from other antibody deficiencies where lymphoid tissue is typically present 1, 2, 4
• The absence or marked reduction of tonsils and lymph nodes is a critical physical finding that should immediately raise suspicion for agammaglobulinemia 1, 4

Family History

• A younger relative dying of similar disease strongly suggests X-linked inheritance, which is seen in XLA affecting maternal male relatives (cousins, uncles, nephews) 1, 2
• Approximately 85% of agammaglobulinemia cases are X-linked (XLA) due to BTK gene mutations 2

Why Other Options Are Less Likely

B - Severe Combined Immunodeficiency (SCID)

• 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 patient's survival to present with 5-6 respiratory infections argues against SCID, which would have caused death much earlier without treatment 1

C - IgA Deficiency

• 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 small tonsils are not characteristic of IgA deficiency, where lymphoid tissue is typically present 1

D - Hyper IgE Syndrome

• Hyper IgE syndrome presents with eczema, recurrent staphylococcal skin abscesses, and pneumatoceles, not primarily respiratory and GI infections 1
• The absence of characteristic skin findings and the pattern of infections do not fit hyper IgE syndrome 1

Immediate Diagnostic Confirmation

Order the following tests immediately to confirm XLA: 1, 2

• Serum immunoglobulin levels (IgG, IgA, IgM) - expect IgG <100 mg/dL, IgA <10 mg/dL, IgM <20 mg/dL 1, 2
• Flow cytometry for CD19+ B cells - expect <2% of lymphocytes 1, 2
• T-cell enumeration - expect normal numbers and function 1, 2
• BTK gene sequencing to confirm the diagnosis 2

Critical Management Priorities

Initiate treatment immediately upon diagnosis without waiting for genetic confirmation: 1, 2

• Start intravenous immunoglobulin (IVIG) replacement therapy at 0.4-0.6 g/kg/month 2, 5
• Aggressive antimicrobial therapy for current infections 1, 2
• Monitor pulmonary status carefully to prevent bronchiectasis, which develops in 10-20% of patients despite treatment 5, 6
• Watch for CNS enteroviral (ECHO virus) infections, which are specific complications of XLA 1, 2

Common Pitfalls to Avoid

• Do not delay diagnosis waiting for B-cell enumeration if the clinical picture (recurrent bacterial infections + small tonsils + family history) is compelling - initiate treatment based on clinical findings 2
• Earlier diagnosis significantly reduces mortality - for every year delay in treatment initiation, the odds of lower respiratory tract infection increase by 21.6% 6
• Do not confuse with transient hypogammaglobulinemia of infancy, which would not present with undetectable levels of all immunoglobulin classes and such severe infections 2