What is the most likely diagnosis for a patient with recurrent sinopulmonary infections, recurrent gastroenteritis with giardiasis, a family history of a relative dying from infections, growth retardation (below 3rd centile for weight and height), and no lymphadenopathy?

X-linked Agammaglobulinemia (XLA)

The most likely diagnosis is B - X-linked agammaglobulinemia (XLA), given the combination of recurrent sinopulmonary infections, recurrent gastroenteritis with giardiasis (indicating susceptibility to encapsulated bacteria and enteric pathogens), positive family history of death from infections, severe growth retardation, and notably the absence of lymphadenopathy. 1

Key Diagnostic Features Supporting XLA

Clinical Presentation Pattern

• Recurrent sinopulmonary infections are the hallmark of humoral immunodeficiency, specifically XLA, where bacterial infections of the upper and lower respiratory tract predominate 2, 1
• The presence of recurrent gastroenteritis with giardiasis is characteristic of agammaglobulinemia (35% of XLA patients have GI tract infections), as these patients lack protective antibodies against enteric pathogens 3
• Growth retardation (weight and height below 3rd centile) is a prominent sign of XLA at diagnosis, reflecting chronic infection burden and malnutrition 4

Critical Distinguishing Feature: Absent Lymphadenopathy

• The absence of lymphadenopathy is pathognomonic for XLA because patients have virtually no B cells and therefore cannot form lymphoid tissue or germinal centers 1
• This single feature effectively excludes SCID and Omenn syndrome, both of which typically present with lymphadenopathy and hepatosplenomegaly due to T-cell infiltration and immune dysregulation 2

Family History

• A positive family history of death from infections strongly suggests X-linked inheritance, with XLA accounting for 85% of all agammaglobulinemia cases 2, 1
• The X-linked pattern means affected males in the maternal lineage, which aligns with a relative dying from infections 1

Why Not SCID?

SCID Would Present Differently

• SCID typically presents within the first 3-6 months of life with opportunistic infections (Pneumocystis jirovecii, CMV, fungal infections), not just encapsulated bacteria 2
• SCID patients characteristically have chronic diarrhea and failure to thrive from birth, but they also develop lymphadenopathy, hepatosplenomegaly, and often skin manifestations 2
• The absence of lymphadenopathy essentially rules out SCID, as these patients have lymphocytic infiltration of tissues despite immune dysfunction 2

Why Not Omenn Syndrome?

Omenn Syndrome Has Distinct Features

• Omenn syndrome presents in early infancy (typically first few weeks) with erythroderma, alopecia, hepatosplenomegaly, and prominent lymphadenopathy due to oligoclonal T-cell expansion 2
• The absence of lymphadenopathy excludes Omenn syndrome, which is characterized by massive lymphoid infiltration 2
• Omenn syndrome patients have eosinophilia and elevated IgE, features not mentioned in this case 2

Confirmatory Laboratory Findings Expected in XLA

Immunoglobulin Profile

• Undetectable or extremely low IgG, IgA, and IgM levels (IgG typically <200 mg/dL) are diagnostic when combined with the clinical picture 1
• The combination of absent immunoglobulins across all classes with normal T-cell counts confirms agammaglobulinemia 1

B-Cell Enumeration

• Peripheral blood CD19+ B-cell counts <2% is characteristic and virtually diagnostic of XLA 1
• This finding distinguishes XLA from other antibody deficiencies like CVID, which typically has normal or only moderately reduced B-cell numbers 5, 6

T-Cell Function

• T-cell numbers and function are normal in XLA, which distinguishes it from SCID where both T and B cells are affected 2, 1

Immediate Management Priorities

Urgent Interventions Required

• Initiate IgG replacement therapy immediately (0.4-0.6 g/kg every 3-4 weeks intravenously or weekly subcutaneously) to prevent further infections and complications 1
• Aggressive antimicrobial therapy for active infections is essential, as these patients cannot mount antibody responses 1
• Do not delay treatment waiting for genetic confirmation—the clinical picture with undetectable immunoglobulins is sufficient to begin therapy 1

Specific Infection Monitoring

• Monitor vigilantly for enteroviral infections, particularly CNS ECHO virus infections, which are specific life-threatening complications of XLA 1
• Patients with XLA are at risk for chronic viral infections including vaccine-strain polio, which can cause a poliomyelitis-like syndrome 4

Common Pitfalls to Avoid

Diagnostic Errors

• Do not confuse with transient hypogammaglobulinemia of infancy, which would not present with undetectable levels of all three immunoglobulin classes and would not have such severe infections 1
• Do not wait for B-cell enumeration if immunoglobulin levels are in the agammaglobulinemic range—begin treatment based on clinical presentation and immunoglobulin levels 1

Recognition Delays

• Under-recognition of recurrent infections and failure to obtain relevant family history are the most important barriers to timely diagnosis of XLA 7
• The mean age at diagnosis is often delayed (6 years in some series), leading to preventable complications including chronic lung disease 4, 7

Long-term Complications

• Chronic pulmonary disease with resultant cardiac failure is the leading cause of death in XLA patients, emphasizing the need for early diagnosis and aggressive treatment 3
• Bronchiectasis develops from repeated respiratory infections, making early intervention critical to preserve lung function 3