Clinical Guidance

No strong correlation is observed between the specific BTK pathogenic variant and the severity of disease; however, individuals who have amino acid substitutions or splice defects that occur at sites that are conserved (but not invariant) tend to be older at the time of diagnosis, and have higher serum concentrations of IgM and slightly more B cells in the peripheral circulation .

Source: GeneReviews — "X-Linked Agammaglobulinemia"

Diagnostic Criteria

Suggestive Findings

X-linked agammaglobulinemia (XLA) should be suspected in probands with the following clinical, laboratory, and family history findings.

Clinical findings

• Recurrent otitis, pneumonitis, sinusitis, and conjunctivitis starting before age five years

• A severe life-threatening bacterial infection such as sepsis, meningitis, cellulitis, or empyema

• Paucity of lymphoid tissue (small adenoids, tonsils, and lymph nodes on physical examination)

Laboratory findings

Source: GeneReviews — "X-Linked Agammaglobulinemia"

Differential Diagnosis

X-linked agammaglobulinemia (XLA) is the most common cause of agammaglobulinemia, accounting for approximately 85% of individuals with early onset of infections, panhypogammaglobulinemia, and markedly reduced numbers of B lymphocytes (CD19+ cells) in the peripheral circulation (2%) . The majority of females with an XLA-like phenotype and males with an XLA phenotype who do not have an identifiable BTK pathogenic variant are likely to have defects in other genes required for normal B cell development . These forms of agammaglobulinemia are very rare. Individuals with agammaglobulinemia caused by pathogenic variants in genes other than BTK cannot be distinguished by routine clinical or laboratory tests from individuals with XLA . These disorders should be considered in females who have an XLA-like phenotype or in males who were presumed to have XLA but who do not have a pathogenic variant in BTK. Families with a known history of consanguinity are more likely to have rare autosomal recessive forms of agammaglobulinemia than XLA. The underlying defect remains unknown in a small percentage of individuals with congenital agammaglobulinemia and absent B cells . Table 2. X-Linked Agammaglobulinemia: Genes of Interest in the Differential Diagnosis of Congenital Agammaglobulinemia and Absent B Cells

Management Guidelines

No clinical practice guidelines specific for X-linked agammaglobulinemia (XLA) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with XLA, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. X-Linked Agammaglobulinemia: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "X-Linked Agammaglobulinemia"

Clinical Guidance

Live viral vaccines, particularly oral polio vaccine, should be avoided in individuals with XLA.

Source: GeneReviews — "X-Linked Agammaglobulinemia"

Therapies Under Investigation

Research studies exploring virus-mediated and oligonucleotide gene therapy for XLA have been conducted in mice [, , , ], but it is not clear when this type of treatment may be available for humans. Gene editing of hematopoietic stem cells is also being developed but to date is not clinically available for XLA treatment . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "X-Linked Agammaglobulinemia"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 6.

X-Linked Agammaglobulinemia: Recommended Surveillance

System/Concern | Evaluation | Frequency

Immunodeficiency

| • CBC w/differential

• Quantitative serum immunoglobulins to monitor gammaglobulin substitution therapy1

| At least annually

Respiratory

| • Chest radiographs or chest CT to assess for chronic lung disease

• Sinus imaging

| As needed

CBC = complete blood count

1. If the individual is stable, the serum IgG does not need to be evaluated with every infusion of gammaglobulin.

Source: GeneReviews — "X-Linked Agammaglobulinemia"