eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Bruton Agammaglobulinemia

Author: Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Contributor Information and Disclosures

Updated: Sep 3, 2008

Introduction

Background

Bruton agammaglobulinemia was the first primary immunodeficiency disease to be described. In 1952, Colonel Ogden Bruton noted the absence of immunoglobulins (Ig) in a boy with a history of pneumonia and other bacterial sinopulmonary infections.1 Bruton was also the first physician to provide specific immunotherapy for this X-linked disorder by administering intramuscular injections of IgG. The patient improved but succumbed to chronic pulmonary disease in his fourth decade of life.

This disorder is now formally referred to as X-linked agammaglobulinemia (XLA), and the gene defect has been mapped to the gene that codes for Bruton tyrosine kinase (Btk) at band Xq21.3. The BTK gene is large and consists of 19 exons that encode the 659 amino acids that form the Btk cytosolic tyrosine kinase. Mutations can occur in any area of the gene. Btk is required for the proliferation and differentiation of B lymphocytes.

In the absence of functional Btk, mature B cells that express surface Ig and the marker CD19 are few to absent. The absence of CD19 is readily detected with fluorocytometric assays, and this finding usually easily confirms the diagnosis of XLA in a male. As Bruton originally described, XLA manifests as pneumonia and other bacterial sinopulmonary infections in 80% of cases.1 Such infections that begin in male infants as maternal IgG antibodies, acquired transplacentally, are lost. Thus, XLA is most likely to be diagnosed when unusually severe or recurrent sinopulmonary infections occur in a male infant younger than 1 year.

In some individuals, the diagnosis is delayed into adulthood. In some cases, this delay can be explained by the variable severity of XLA, even within families in which the same mutation is present. However, a significant contributing factor is the deceptively poor inflammatory response seen in the absence of antibodies. Delayed diagnosis puts patients at risk for chronic pulmonary disease and poor growth, leading to mortality at a younger age. Encapsulated bacteria, most commonly Streptococcus pneumoniae, followed by Haemophilus influenzae type b and staphylococcal species, are the typical pathogens.

Pathophysiology

In the absence of mature B cells, patients lack lymphoid tissue and fail to develop plasma cells, the cells that manufacture antibodies. Germinal centers where B cells proliferate and differentiate are poorly developed in all lymphoid tissue, including the spleen. Tonsils, adenoids, peripheral lymph nodes, and Peyer patches in the intestines are all small or absent. The lungs and the lamina propria of the gut lack the normal pattern of lymphocyte distribution. However, biopsy of lymphoid tissue and bone marrow examination are not currently performed in the workup of most cases of XLA and other forms of hypogammaglobulinemia.

Animal models of human BTK mutations are confined to mice at this time. Mouse models have milder disease than humans. However, murine models, including knockout and transgenic mice, have been useful in understanding the mechanisms of B lymphopoiesis, B-cell differentiation, and antibody formation. Murine gene mutations in human counterparts may be associated with a clinical illness different from the illness seen in mice.

Although defects may occur in many steps in B-cell development and maturation, resulting in agammaglobulinemia, the most common and well-described defect is the impaired maturation of the pro–B cells to pre–B cells. In the fetal bone marrow, the first committed cell in B-cell lineage is the early pro–B cell, which is identified by its ability to proliferate in the presence of interleukin (IL)-7. These cells develop into late pro–B cells, in which rearrangement of the heavy chain occurs. This rearrangement process requires the recombination-activating genes (ie, RAG1 and RAG2); their enzymatic activities are controlled by IL-7 and, perhaps, by other factors.

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

Increasing levels of IgD in the transitional cells finally results in the mature B cell, with both IgM and IgD expressed. 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 of Ig (ie, IgG, IgA, or IgE). Activation of the 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.

Murine B-cell proliferation and differentiation is under the control of BTK, as well as SYK; PAX5; and genes that code for l 5, Ig-a, Ig-b, g chain of IL-2 receptor (IL-2R g), lyn, and bcl-2. Mutations in these mouse genes and in the mouse gene for Btk lead to milder forms of B-cell deficiency compared with that of humans with BTK, m heavy-chain (µH), or l 5 mutations.

Mutations in the murine IL receptor common g chain also cause mild B-cell deficiency in mice. In contrast, mutations in the human IL common g chain cause X-linked severe combined immunodeficiency (SCID), with normal-to-high levels of B cells expressing CD19. 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.

The vital role of Btk in Toll-like receptor (TLR) signaling has been supported by several lines of evidence. Although patients with XLA have normal numbers of circulating dendritic cells, a profound impairment of IL-6 and tumor necrosis factor (TNF)-a production is observed in response to the TLR8 agonist ssRNA.2,3 This may provide an explanation for their increased susceptibility to enteroviral infections. Others have also found defective TLR2, TLR4, and TLR7/8–induced TNF-a production.4 Btk is involved in TLR9 activation and expression.5 Schmidt et al (2006) also showed that Btk is required for TLR-induced IL-10 production.6

Frequency

United States

The estimated birth rate of XLA in the United States was calculated to be 1 case per 379,000 live births.7 A prevalence of 1 case per 250,000 individuals has been estimated in the United States. However, this number was reviewed prior to the availability of mutational analysis and is generally considered to be an underestimate. New mutations are believed to cause 30-50% of XLA cases.

International

Geneticists believe that the prevalence of XLA is similar among most ethnic groups. Data from France have suggested a prevalence of 1 case per 70,000-90,000 population. The greater frequency in France may well be related to more accurate acquisition of statistics. Black, Japanese, and Malaysian populations have lower reported frequencies of clinical XLA, but whether these frequencies are accurate is debatable because of the genetic mechanisms that cause XLA.

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 fifth decade of life.

Viral and pulmonary infections cause more than 90% of mortalities. Malignancies are unusual in XLA, although lymphoreticular malignancies associated with XLA were previously reported in tumor registries.

  • Chronic enteroviral infections are the most common etiology for early morbidity. High-dose IVIG or Ig administered intrathecally has slowed, but not stopped, the progression of CNS deterioration. Dementia, ataxia, and paresthesias are the common clinical features of meningoencephalitis due to enteroviruses. Other viral causes of death are sporadic. Adenoviruses are well-recognized causes of morbidity and mortality in any patient with immunocompromise. Hepatitis viruses are also a risk; hepatitis C has been transmitted by IVIG preparations with inadequate viral inactivation processes. Overall, viral infections resulted in one half of the deaths that occurred in 3 series.
  • Pulmonary infections, both acute and chronic, account for most other deaths. Recurrent pulmonary infections frequently lead to bronchiectasis. Common causative agents include S pneumoniae, H influenzae type b, and Staphylococcus aureus. Burkholderia cepacia and coagulase-negative staphylococci are other significant bacterial agents.
  • If present, inflammatory bowel disease is usually chronic in XLA and leads to malnutrition and cachexia and further increases the risk of infection.

Race

Most investigators have studied northern European populations. Although black, Japanese, and Malaysian populations are reported to have lower risks for XLA, geneticists doubt the accuracy of these statistics. Recently, more reports have detailed Asian8,9 and Arabic populations.10

Sex

XLA is a disorder that affects only males. No carrier female with any clinical illness related to the mutated allele has been identified. Girls with absent mature B cells may have autosomal recessive mutations that affect gene products other than those of BTK (see Agammaglobulinemia).

Age

Because XLA is a genetic disorder, male infants can be identified with prenatal diagnosis when the mother has been identified as a carrier. Chorionic villus sampling (CVS) can be performed early in pregnancy, and DNA analysis can be used when the family's exact mutation is known. Amniocentesis can be performed later in gestation. Collection of fetal lymphocytes through in utero umbilical cord sampling can be used to enumerate CD19+ B cells and mature T cells using fluorocytometric analysis, although this procedure places the fetus at some risk for mortality (ranging from <1-5%). At birth, cord blood can be sent for fluorocytometric analysis of lymphocyte populations. Quantitative IgG levels are not useful; cord and fetal IgG levels largely reflect maternal IgG transported across the placenta.

  • Because of passive transplacental acquisition of maternal IgG, newborns have normal serum IgG levels and may not have problems until the IgG is catabolized. Because newborns cannot produce their own Ig, increased susceptibility to infections usually develops in infants older than about 6 months. Therefore, patients with XLA can clinically present when they are aged 3 months to 5 years. Most cases of XLA are now identified in patients younger than 1 year, depending on the rate of maternal-derived IgG loss and occurrence of infections. The average age of diagnosis is younger in patients with a family history (2.6 y) than in those without (5.4 y).7
  • Patients may also present in the second or third decade of life, although this is uncommon. The oldest age at diagnosis was 51 years. These patients may have milder disease related to the presence of mutated Btk protein rather than complete absence of the protein. Rarely, the individual has mild disease while others with the same mutation have more severe clinical illness.

Clinical

History

All patients with Bruton agammaglobulinemia, now formally termed X-linked agammaglobulinemia (XLA), are males. More than 90% of affected males present with unusually severe or recurrent sinopulmonary infections. Meningitis, osteomyelitis, sepsis, and GI tract infectious (eg, gastroenteritis or diarrhea) are less common initial manifestations of XLA.

  • Infants typically develop recurrent otitis media, pneumonia, and sinusitis before age 1 year. By mid childhood, chronic sinusitis becomes prevalent, and the prevalence of otitis media decreases.
    • Infectious agents involved are usually S pneumonia or H influenzae type b. Both are extracellular encapsulated bacteria. As patients become older, encapsulated bacteria continue to be the most common sources of infection, although staphylococcal infections must also be considered. Neisseria meningitidis and Moraxella catarrhalis, which is not encapsulated, are other bacteria whose portal of entry is the respiratory tract.
    • A chronic cough in a patient may indicate a risk for chronic pulmonary disease, which may be restrictive, obstructive, or both.
    • Infections due to Mycoplasma and Ureaplasma species have been reported in both adolescents and adults.
  • The child may also have diarrhea that is not completely explained by frequent antibiotic use.
    • Many patients have diarrhea caused by Giardia or Campylobacter species, and management of the diarrhea is difficult, even with appropriate therapy.
    • Chronic bacteremia and skin infections caused by Helicobacter and related species (eg, Flexispira, Campylobacter) in patients with XLA are now appreciated.11 Campylobacter infection can also be associated with a reactive arthritis in patients with XLA.12
    • Although patients with agammaglobulinemia are usually able to handle viral infections, they are susceptible to certain viruses that replicate in the GI tract and then spread to the CNS. This indicates the importance of antibody production in limiting the spread of infections with enteroviruses such as poliovirus, echovirus, and coxsackievirus.
  • Patients may present with vaccine-related poliomyelitis after immunization with the live poliovirus vaccine.13
    • Although prolonged secretions of a virus have been described (up to 637 days postvaccination), based on 3 separate studies, poliovirus carrier status among people with primary immune deficiency appears to be rare and may not manifest with disease. Conversely, enteroviral infections are potentially fatal, irrespective of route of acquisition (ie, community acquired or acquired via the live poliovirus vaccine).
    • Katamura et al (2002) described nonprogressive viral myelitis in a patient with XLA and suggested that the prognosis of CNS infections in agammaglobulinemia is not based on the Ig level alone and that they are not always progressive or fatal.14
    • The use of intraventricular infusion of Ig has been well documented in XLA patients with CNS viral infection. However, the infusions have not been documented to prevent death caused by chronic enteroviral infection of the CNS.
  • Invasive fungal and other opportunistic infections remain rare, even in older patients with XLA and debilitating chronic lung or GI disease.
  • Autoimmune disorders may be associated with infections at the patient's initial presentation or may develop in older patients.
    • Inflammatory bowel disease is particularly common.
    • Other autoimmune disorders include cytopenias.
    • Arthritis indistinguishable from juvenile rheumatoid arthritis (JRA) may be the presenting manifestation in patients with XLA.
    • Evaluating for chronic infectious processes is essential. Mycoplasmal infection is a common cause of severe chronic erosive arthritis. Patients with mild cases rapidly respond to antimicrobial therapy, such as tetracycline. In more severe cases, arthritis may improve following treatment with IVIG.
  • Interestingly, malignancies are rare and are not currently a significant cause of mortality.
  • A family history of other affected males should be sought because approximately one third of affected patients have an affected family member.8 However, female carriers have no clinical manifestations related to their mutated allele.

Physical

Infants and older patients with XLA typically appear healthy. In healthy infants, lymphoid tissues such as tonsils and peripheral lymph nodes are poorly developed; therefore, the absence of these tissues is not noted until patients are toddlers. A poor local inflammatory response also compromises the usefulness of physical examination findings. For example, patients may have hypoplastic tonsils and lymph nodes that fail to undergo normal hypertrophy in response to infection. Therefore, physicians should suspect XLA in male infants who have unusually severe pneumonias associated with bacteremia or who have unusually frequent otitis media, chronic cough, or congestion. The last 2 symptoms typically respond to antibiotic therapy in a timely fashion but may soon recur.

  • In a study by Sikora and Lee (2003), up to 48% of patients developed sinusitis. Upon examination, patients may have hypoplastic tonsils and lymph nodes that fail to undergo normal hypertrophy in response to infection.15
  • Staphylococcal conjunctivitis and skin infections are less common than sinopulmonary infections, but they may also be part of the initial presentation in patients with XLA. These staphylococcal infections are less useful for discriminating XLA from other illnesses because they are frequently present in immunocompetent individuals and in individuals with other primary immunodeficiencies such as hyperimmunoglobulin E (hyper-IgE) syndrome and other antibody deficiencies.
  • Diarrhea caused by Giardia species is part of the classic presentation in any patient with antibody deficiency disease. Patients with XLA have an increased risk for other infectious etiologies of diarrhea, including Campylobacter jejuni, Shigella species, and Salmonella species. Infections due to these organisms seem to respond less well to medical therapy and also seem to become chronic more often in patients with antibody deficiency diseases than in others.
  • Rarely, patients with XLA also have a short stature caused by a deficiency in growth hormone. A newly discovered mutation in myeloid elf-1–like factor may be responsible for the disease.16 These patients must be distinguished from patients with XLA who have poor growth secondary to malnutrition.

Causes

As discussed in Pathophysiology, the disease is caused by impaired function of Btk. The exact mutation of BTK is detected with mutational analysis using single-strand conformation polymorphism (SSCP), chemical cleavage of mismatch (CCM), denaturing gradient gel electrophoresis (DGGE), reverse transcriptase polymerase chain reaction (RT-PCR), or direct DNA analysis. DNA analysis has the advantage of easier transport of purified DNA obtained from the patient and can be used to detect splice defects in addition to the more common missense and nonsense mutations, deletions, or insertions. If a mutation in BTK cannot be found, the absence of BTK RNA or protein is considered the criterion standard for validating a diagnosis of XLA.

Mutations in BTK are found in all areas of the gene. The pleckstrin homology region, the tyrosine kinase region, and areas referred to as Src homology domains (SH1, SH2, and SH3) are all important for gene function. Defects in these exons are most common. Splice defects that involve introns account for fewer than 20% of the abnormalities. Rare mutations in the promoter upstream region have been described. In some milder cases of XLA, the Btk protein is still present, although in a mutated form and in lesser amounts. However, no genotype-phenotype correlation has been found. Mutations of BTK account for 85-90% of patients with early onset agammaglobulinemia and an absence of B cells.

More on Bruton Agammaglobulinemia

Overview: Bruton Agammaglobulinemia
Differential Diagnoses & Workup: Bruton Agammaglobulinemia
Treatment & Medication: Bruton Agammaglobulinemia
Follow-up: Bruton Agammaglobulinemia
Multimedia: Bruton Agammaglobulinemia
References
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Further Reading

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Keywords

Bruton agammaglobulinemia, Bruton's agammaglobulinemia, severe combined immunodeficiency, X-linked agammaglobulinemia, XLA, Bruton type agammaglobulinemia, X-linked hypogammaglobulinemia, X-linked infantile hypogammaglobulinemia, Bruton disease, Bruton's disease, congenital agammaglobulinemia, Glanzmann-Riniker syndrome, primary agammaglobulinemia, pneumonia, Streptococcus pneumoniae, Haemophilus influenzae, meningoencephalitis, enterovirus, bronchiectasis, inflammatory bowel disease, malnutrition, meningitis, osteomyelitis, sepsis, gastroenteritis, diarrhea, otitis media, sinusitis, Mycoplasma, Ureaplasma, Giardia, Campylobacter, bacteremia, reactive arthritis, poliomyelitis

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Contributor Information and Disclosures

Author

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Terry Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: "no financial interest" None None

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services
John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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