Abstract
BackgroundCommon variable immune deficiency (CVID), one of the most common primary immunodeficiency diseases presents in adults, whereas X-linked agammaglobulinemia (XLA), an inherited humoral immunodeficiency, is usually diagnosed early in life after maternal Igs have waned. However, there have been several reports in the world literature in which individuals have either had a delay in onset of symptoms or have been misdiagnosed with CVID and then later found to have mutations in Bruton's tyrosine kinase (BTK) yielding a reclassification as adult-onset variants of XLA. The typical finding of absent B cells should suggest XLA rather than CVID and may be a sensitive test to detect this condition, leading to the more specific test (Btk mutational analysis). Further confirmation may be by mutational analyses.MethodsThe records of 2 patients were reviewed and appropriate clinical data collected. BTK mutational analysis was carried out to investigate the suspicion of adult-presentation of XLA. A review of the world literature on delayed diagnosis of XLA and mild or "leaky" phenotype was performed.Results2 patients previously diagnosed with CVID associated with virtual absence of CD19+ B cells were reclassified as having a delayed diagnosis and adult-presentation of XLA. Patient 1, a 64 yr old male with recurrent sinobronchial infections had a low level of serum IgG of 360 mg/dl (normal 736–1900), IgA <27 mg/dl (normal 90–474), and IgM <25 mg/dl (normal 50–415). Patient 2, a 46 yr old male with recurrent sinopulmonary infections had low IgG of 260 mg/dl, low IgA <16 mg/dl, and normal IgM. Mutational analysis of BTK was carried out in both patients and confirmed the diagnosis of XLAConclusionThese two cases represent an unusual adult-presentation of XLA, a humoral immunodeficiency usually diagnosed in childhood and the need to further investigate a suspicion of XLA in adult males with CVID particularly those associated with low to absent CD19+ B cells. A diagnosis of XLA can have significant implications including family counseling, detecting female carriers, and early intervention and treatment of affected male descendents.
Highlights
Common variable immune deficiency (CVID), one of the most common primary immunodeficiency diseases presents in adults, whereas X-linked agammaglobulinemia (XLA), an inherited humoral immunodeficiency, is usually diagnosed early in life after maternal Igs have waned
The results demonstrated a hemizygous point mutation associated with a single amino acid change in the Src homology 1 (SH1) domain of the Bruton's tyrosine kinase (Btk) gene confirming a diagnosis of XLA (Table 2)
We present two males diagnosed in adulthood with CVID whom upon further investigation by Bruton's tyrosine kinase (BTK)
Summary
Common variable immune deficiency (CVID), one of the most common primary immunodeficiency diseases presents in adults, whereas X-linked agammaglobulinemia (XLA), an inherited humoral immunodeficiency, is usually diagnosed early in life after maternal Igs have waned. Primary humoral immune deficiency disorders are characterized by defects in antibody production leading to significantly weakened humoral immunity These patients are highly susceptible to recurrent bacterial infections, bacteremia, and sepsis resulting in high mortality rates. Among these disorders there is heterogeneity of clinical manifestations and immunological defects observed. Xlinked agammaglobulinemia (XLA), a disorder of infants and children, sometimes may be diagnosed late in life In this instance, it may be confused for another disorder-common variable immune deficiency (CVID). Though the clinical and prognostic outcomes may be considered to be similar in the two disorders, the genetic basis is different, leading one to evaluate family transmission more aggressively or consider gene therapy as an option in one or more of these conditions
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