Agammaglobulinemia is a form of primary immunodeficiency demarcated by defects in B-cell function due to gene mutations encoding the Bruton tyrosine kinase protein on chromosome X, which is why the term X-linked agammaglobulinemia is used in the literature. Recurrent bacterial infections of the skin, lungs and the gastrointestinal tract appearing in infancy are the main clinical presentation. The diagnosis is made based on clinical and laboratory criteria, as well as genetic studies.
Signs and symptoms of agammaglobulinemia (often referred as X-linked agammaglobulinemia, or XLA) start to appear several months after birth (between 7-9 months of age in most cases) when maternal immunoglobulins in the child slowly begin to disappear, and are completely absent at the end of the child's first year of life [1] [2]. Having in mind the complete or near-complete dysfunction of B-cells due to mutations in the Bruton tyrosine kinase (BTK) protein, situated on the X chromosome (resulting in almost exclusive appearance of the disease in males), infants are predisposed to numerous infections of bacterial, viral and fungal origin, and their recurrent appearance is usually the first and most important clinical presentation [3] [4]. In particular, patients are most susceptible to infections caused by encapsulated bacteria (such as streptococcus pneumoniae, haemophilus influenzae, and pseudomonas aeruginosa), mycoplasma spp., enteroviruses and giardia lamblia [4] [5]. Recurrent infections of the respiratory system (pneumonia and less commonly sinusitis), skin, the gastrointestinal tract (caused by rotavirus, salmonella spp., and campylobacter spp., in addition to giardiasis) are typical for agammaglobulinemia patients, and recurrent otitis media is described in the vast majority of cases [1] [4] [6]. Central nervous system (CNS) infections, both meningitis, and encephalitis, as well as sepsis and infections of the musculoskeletal system (osteomyelitis and arthritis), can develop in the absence of a timely diagnosis [1] [4] [6]. Hand-foot-and-mouth disease, hepatitis, opportunistic infections (pneumocystis jiroveci pneumonia - PCP) and polio vaccine-related poliomyelitis (as a result of depleted B-cells) are very rare manifestations of agammaglobulinemia but have been reported by certain authors [1] [4] [7].
The diagnosis of agammaglobulinemia can be made only if physicians recognize the recurrent nature of infections in infancy and early childhood and order a thorough laboratory investigation. Despite evident clinical criteria for some form of immunodeficiency, however, up to 20% of children are not diagnosed by school age, indicating that clinical suspicion is probably the most important factor in detecting agammaglobulinemia [1] [3] [6]. A detailed patient history focused on the interview with the parents (as children are often too young to provide relevant information) can provide vital clues for the physician. A detailed family history is equally important and may be quite useful in determining whether close family members have or had the diagnosis or experience of similar symptoms, as a significant number of patients have a confirmed family member suffering from agammaglobulinemia [6]. Initial laboratory testing reveals neutropenia in about 15% of cases, whereas reductions in serum immunoglobulins (IgG, IgM and IgA) are readily encountered [1] [5] [6] [8]. A key diagnostic feature of agammaglobulinemia is a markedly lower number of CD19+ B cells (< 2%), while absent isohemagglutinins and/or poor vaccine responses are also important features that make the diagnosis of this primary immunodeficiency highly likely [1] [8]. Confirmation of agammaglobulinemia, however, is achieved by detecting BTK mutations through genetic studies in both the patient and in one of his maternal cousins [1].