A 9-month-old boy is brought to the office due to 3 days of fever. In the past 3 months, the patient has had an episode of acute otitis media and an episode of lobar pneumonia that required hospitalization and prolonged intravenous antibiotic therapy. He is at the 40th percentile for weight. Temperature is 38.2 C (100.8 F). Physical examination reveals a bulging, erythematous tympanic membrane in the right ear but is otherwise unremarkable. Laboratory results are as follows:
| Complete blood count | ||
| Leukocytes | 8,000/mm3 | |
| Neutrophils | 6,000/mm3 | |
| Lymphocytes | 2,000/mm3 | |
| Immunologic and rheumatologic studies | ||
| Immunoglobulins | ||
| IgG | 80 mg/dL | (650-1,500 mg/dL) |
| IgA | 10 mg/dL | (76-390 mg/dL) |
| IgM | 11 mg/dL | (40-345 mg/dL) |
| IgE | 2 mg/dL | (0-380 mg/dL) |
| Lymphocytes | ||
| CD4+ cell count | 1,150 cells/mm3 | (640-1,175 cells/mm3) |
| CD8+ cell count | 810 cells/mm3 | (335-875 cells/mm3) |
| CD19+ cell count | 38 cells/mm3 | (226-370 cells/mm3) |
Which of the following is the most likely diagnosis for this patient?
Humoral immunodeficiency syndromes | |||||
Condition | B cell | IgG | IgA | IgM | IgE |
Selective IgA deficiency | Normal | Normal | ↓ | Normal | Normal |
Job syndrome | Normal | Normal | Normal | Normal | ↑ |
CD40 ligand deficiency | Normal | ↓ | ↓ | ↑ | ↓ |
Common variable | Normal | ↓ | ↓ | ↓ | ↓ |
X-linked | ↓ | ↓ | ↓ | ↓ | ↓ |
This infant has recurrent sinopulmonary infections, markedly low serum immunoglobulins, and decreased B cells. These findings are consistent with X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, a genetic disorder characterized by a defect in tyrosine kinase in B cells. This defect results in failure of bone marrow pre-B cells to mature into circulating CD19+ B cells, leading to low immunoglobulin production.
When protection from maternally derived transplacental IgG antibodies wanes at age 3-6 months, patients with XLA develop recurrent sinopulmonary (eg, acute otitis media, pneumonia) and gastrointestinal (eg, Salmonella, Campylobacter, Giardia) infections. Physical examination in children age >2 with XLA is remarkable for underdeveloped or absent lymphoid tissue (eg, tonsils, adenoids). Notably, these tissues are not prominent even in healthy children age <2.
Laboratory findings consistent with XLA include low serum IgG, IgM, and IgA, impaired antibody response to vaccines, and markedly reduced CD19+ B cells; T-cell count is normal. Detection of BTK gene mutation confirms the diagnosis. Treatment is immunoglobulin replacement therapy (eg, intravenous immunoglobulin) with or without prophylactic antibiotics.
(Choice A) CD40 ligand deficiency (X-linked hyper-IgM syndrome) presents in infancy with recurrent sinopulmonary infections and is characterized by low IgG and elevated IgM due to defective class-switch recombination. This patient's low IgM makes this diagnosis unlikely.
(Choice B) Common variable immunodeficiency causes recurrent infections due to low IgG, IgM, and IgA but typically does not present until after adolescence. In addition, differentiation of B cells into plasma cells is impaired, but CD19+ B-cell concentration is normal.
(Choice C) Severe combined immunodeficiency (SCID) is caused by impaired T-cell development and subsequent B-cell dysfunction. Affected patients develop life-threatening bacterial, viral, fungal, and opportunistic infections in infancy. B- and T-cell concentrations are markedly decreased in SCID.
(Choice D) Transient hypogammaglobulinemia of infancy is characterized by decreased IgG, variable IgM, and normal IgA and B-cell concentrations. Affected patients develop mild, recurrent sinopulmonary and gastrointestinal infections. Immunoglobulin levels generally normalize by age 9-15 months.
(Choice E) Wiskott-Aldrich syndrome is an X-linked disorder characterized by immunodeficiency, microthrombocytopenia, and eczema. B and T cells are classically decreased but may be normal in infancy, and immunoglobulin profile shows low to normal IgG and IgM with elevated IgA and IgE.
Educational objective:
X-linked (or Bruton) agammaglobulinemia presents with recurrent sinopulmonary or gastrointestinal infections in late infancy. Serum immunoglobulins and B cells are markedly low to absent.