Agammaglobulinemia

Updated: May 06, 2014
  • Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD  more...
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Overview

Background

Agammaglobulinemia, or hypogammaglobulinemia, is the most common of the primary immunodeficiencies, accounting for approximately 50% of cases. Three major types can be described: X-linked, early onset, and late onset. After more than 50 years since the clinical entity was first described by Bruton in 1952, the molecular defect in X-linked agammaglobulinemia (XLA) has been elucidated. In Bruton's honor, the gene responsible has been named Btk, which stands for Bruton tyrosine kinase. Several historical reviews have been written. [1, 2]

An estimated 90% of patients with early-onset agammaglobulinemia and absence of B cells have abnormalities in the Btk gene (ie, Bruton agammaglobulinemia or XLA). XLA is further discussed in detail in the article Bruton Agammaglobulinemia. Late-onset disease is usually referred to as common variable immunodeficiency (CVID), also described separately. However, reports are increasing of adults who are diagnosed with XLA. An approach in evaluating an adult with hypogammaglobulinemia has been published [3] and possible molecular-genetic mechanisms speculated. [4]

The remaining type is early onset non–Bruton agammaglobulinemia, with low or absent serum immunoglobulin (Ig). Most cases are agammaglobulinemia with autosomal recessive/dominant heritage and represent a very heterogeneous group, including immunoglobulin (Ig) deficiency with increased immunoglobulin M (hyper-IgM syndrome), which is also discussed separately (see X-linked Immunodeficiency With Hyper IgM). In addition, some infants have an initially low Ig level that eventually increases to normal levels. This is known as transient hypogammaglobulinemia of infancy and is discussed in detail in a separate article.

Defective antibody production and low circulating numbers of B cells were described in some female infants and in males in whom no Btk abnormalities were detected. These observations imply the involvement of other genes. This article describes the cases of agammaglobulinemia caused by defects other than Btk. However, because the clinical manifestations and treatments are similar, information from Btk -deficient patients is included because of the lack of sufficient numbers of such patients. Finally, some conditions secondary to acquired immunodeficiency are also described because they need to be recognized in addition to the primary diseases. For other B-cell defects, such as specific Ig deficiencies (eg, immunoglobulin A [IgA] or immunoglobulin G [IgG] subclass deficiencies), refer to the article B-Cell Disorders.

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Pathophysiology

Although defects may occur in many steps in B-cell development and maturation resulting in the lack of Ig production, the most common and well-described defect is the one at the stage of pro–B-cell to pre–B-cell maturation (see the image below).

Early stages of B-cell differentiation can be iden Early stages of B-cell differentiation can be identified by the status of the immunoglobulin genes and by the cell surface markers CD34, CD19, and surface immunoglobulin (sIg). From: Conley ME. Genes required for B cell development. J Clin Invest. 2003;112: 1636-8. Reproduced with permission of American Society for Clinical Investigation via Copyright Clearance Center.

In the fetal bone marrow, the first committed cell in B-cell development is the early pro-B cell, identified by its ability to proliferate in the presence of interleukin-7 (IL-7). These cells develop into late pro–B cells in which rearrangement of the heavy chain genes occurs. This rearrangement process requires the recombination activating genes RAG1 and RAG2, which are controlled by IL-7 and perhaps other factors.

When the heavy chain is produced, it is transported to the cell surface by the Ig-α (CD79a) and Ig-β (CD82) heterodimers or by the surrogate light chain. Progression from this late pro–B-cell to the pre–B-cell stage involves the rearrangement and joining of the various segments of the heavy chain genes. The completion of rearrangement of the light and heavy chains and the presence of surface IgM results in the immature B cell, which then leaves the bone marrow.

Increasing expression of IgD in the transitional cells finally results in the mature B cell with IgM and IgD both expressed on their cell surface. The mature B cells circulate between secondary lymphoid organs and migrate into lymphoid follicles of the spleen and lymph nodes in response to further stimuli and various chemokines. T cells stimulate B cells to undergo further proliferation and Ig class switching, leading to the expression of the various isotypes IgG, IgA, or immunoglobulin E (IgE).

Mutations on Btk components of the pre–B-cell and B-cell receptor (lambdα5, Ig-α, and Ig-β), or the scaffolding protein BLNK account for approximately 90% of defects in early B-cell development. [5] Mutations in Btk result in Bruton agammaglobulinemia. The defect of µ heavy-chain gene on chromosome 14 is the most frequent abnormality in patients with agammaglobulinemia and decreased B cells but no defect in Btk.

Ig-α and Ig-β are encoded by the mb-1 and B29 genes, respectively. A case involving a female patient with a mutation in the Ig-λ5/14/1 gene that resulted in a defect in the surrogate light chain has also been described.

Other mutations in the components of the pre–B-cell and B-cell antigen receptor complex (eg, defects in the B-cell linker protein [BLNK]) account for 5-7% of patients with defects in early B-cell development. These patients have normal numbers of pro–B cells but no pre–B or mature B cells. Their clinical features are similar to those of patients with XLA.

Activation of B-cell receptor (BCR) induces the recruitment of Syk, which phosphorylates BLNK, a contributor to the activation of Btk that affects other intracellular signaling events.

These findings indicate that a defect in any of the steps in B-cell development may be clinically important. Approximately 85% of patients with defects in early B-cell development have XLA. However, when a female patient presents with absence of serum Ig and peripheral blood B cells, such a patient clearly does not have Bruton agammaglobulinemia or mutations in the Btk gene unless she has XO karyotype. The elucidation of her specific gene defects may shed additional information on B-cell development.

Such a patient was recently described and subsequent whole exome sequencing found a premature stop codon in exon 6 of PIK3R1. [6] She had in absence of p85α but normal expression of the p50 α and p55 α regulatory subunits of P13K. Bone marrow aspirates showed less than 0.01% CD19+ B cells with normal percentages of TdT+VpreB+CD19- B cell precursors.

The exact defects have not yet been determined in other patients in whom agammaglobulinemia has been associated with a mosaic of ring chromosome 18 [7] or hypogammaglobulinemia in a male with ring chromosome 21. [8] Patients with B-cell deficiency associated with intrauterine growth retardation have been described, [9] and patients with agammaglobulinemia with spondyloepiphyseal dysplasia and retinal dystrophy have also been described. [10] The syndrome of X-linked hypogammaglobulinemia with growth hormone deficiency has also been reported. [11] This has been mapped to the same region that encompasses the Btk gene and may involve a gene that controls growth hormone production, implying a small contiguous gene deletion that includes both the gene for XLA and another closely linked gene involved in growth hormone production. The structural gene for growth hormone is located on the long arm of chromosome 17.

In addition to the genetic defects described above, other pathophysiology mechanisms may result in hypogammaglobulinemia or agammaglobulinemia, such as viral infections, malignancy, or drug effects. These are described in more detail in Causes.

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Epidemiology

Frequency

United States

Agammaglobulinemia occurs in approximately 1 in 250,000 males in the United States.

International

In a study of serum Ig levels in 2000 consecutive patients in Saudi Arabia, agammaglobulinemia was diagnosed at a rate of 250 cases per 100,000 individuals. [12] These patients accounted for 16% of the primary humoral immunodeficiency groups (with selective IgA at 45%, CVID at 29%, and selective IgG at 10%). In contrast, the prevalence of primary immunodeficiency disorders in Morocco was only 0.81/100,000 inhabitants, indicating significant underdiagnosis. [13]

In Caucasians, between 60 and 70% of primary immunodeficiencies are antibody-deficiencies.

In Brazil, of 101 cases of humoral deficiencies, XLA was the least frequent (9), compared with IgA deficiency (60) and transient hypogammaglobulinemia (14). [14]

In Asians, specifically in Hong Kong, humoral defects were identified in 50 of 117 patients diagnosed with primary immunodeficiency. [15] A similar percentage was seen in China, [16] but the rate was slightly higher (60%) in Sri Lanka, with 29% CVID and 21% XLA. [17]

Mortality/Morbidity

Patients who received intravenous IgG (IVIG) before age 5 years have lower morbidity and mortality rates than previously identified patients who were treated only with fresh-frozen plasma (FFP) and intramuscular Ig (IMIG); achieving IgG levels near normal or even above 200 mg/dL is difficult using FFP or IMIG. Patients who receive IVIG or subcutaneous IgG (SCIG) therapy regularly may have a near-normal lifestyle. Patients are known to survive into the seventh decade of life.

Viral and pulmonary infections cause more than 90% of mortalities. Patients with agammaglobulinemia are at risk of frequent and recurrent infections. Severe bacterial infections resulting in pneumonias or meningitis and subsequent bacteremia could be fatal; however, the major causes of morbidity are chronic upper pulmonary disease (eg, sinusitis) or lower pulmonary disease (eg, bronchiectasis).

In patients with agammaglobulinemia, one study indicated that, although the incidence of bacterial infections resulting in hospitalization decreased from 0.40-0.06 per patient per year during intravenous Ig replacement, chronic sinusitis and bronchiectasis continue to occur.

Central nervous enteroviral infections can be especially disabling, resulting in a long-term CNS debilitating state.

Autoimmune and allergic manifestations are another source of morbidity in these patients.

Sex

Agammaglobulinemia can be either X-linked (XLA) or autosomal recessive. XLA is more often recognized as Bruton agammaglobulinemia. In a large European study involving 46 centers in 18 countries, hypogammaglobulinemia was the most common primary immunodeficiency disease (excluding agammaglobulinemia). Males accounted for 63% of this group of 2076 children. [18]

Age

Because of passive, transplacental acquisition of maternal IgG, newborns have normal levels of serum IgG and do not have problems until the IgG is catabolized. Because newborns cannot produce their own Ig, increased susceptibility to infections develops in infants older than 6 months. Patients with non-Btk mutations tend to be younger at the time of diagnosis, and they are more likely to have severe complications.

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