Agammaglobulinemia

Agammaglobulinemia
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.

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.

The remaining type is early-onset non–Bruton agammaglobulinemia, with low or absent serum immunoglobulin (Ig). Most cases are autosomal agammaglobulinemia and represent a very heterogeneous group, including 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.

Recently, 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, since the clinical manifestations and treatments are similar, information from Btk-deficient patients is included because of the lack of sufficient patients. Finally, some secondary immunodeficiency situations are also described because these 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.

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 maturation of the pro–B cell to pre–B cell (see Image 1). 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 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-a (CD79a) and Ig-b (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. 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 levels of immunoglobulin D (IgD) in the transitional cells finally results in the mature B cell with IgM and IgD both 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 IgG, IgA, or immunoglobulin E (IgE).
The m heavy-chain gene on chromosome 14 is the most frequent abnormality in a patient with agammaglobulinemia and decreased B cells who does not have a defect in Btk. Ig- a and Ig-b are encoded by the mb-1 and B29 genes, respectively. A case involving a female patient with a mutation in the Ig-a gene has been described. A case involving a male patient with hypogammaglobulinemia caused by mutation at the l5/14/1 gene, resulting 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. Clinically, they are not different from 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 has an absence of serum Ig and peripheral blood B cells, the patient clearly does not have Bruton agammaglobulinemia or mutations in the Btk gene. The elucidation of her specific gene defects may shed additional information on B-cell development.

The exact defects have not yet been determined in other patients in whom agammaglobulinemia has been associated with a mosaic of ring chromosome 18 (Litzman, 1998) or hypogammaglobulinemia in a male with ring chromosome 21 (Ohga, 1997). Patients with B-cell deficiency associated with intrauterine growth retardation have been described (Revy, 2000), and patients with agammaglobulinemia with spondyloepiphyseal dysplasia and retinal dystrophy have also been described (Roifman, 1999). The syndrome of X-linked hypogammaglobulinemia with growth hormone deficiency also exists. This has been mapped to the same region that encompasses the Btk gene and may involve a gene controlling 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. Note that 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.

Frequency:
- In the US: Agammaglobulinemia occurs in approximately 1 in 250,000 males in the United States.
- Internationally: In a study of serum Ig levels in 2000 consecutive patients in Saudi Arabia, agammaglobulinemia was diagnosed at a rate of 250 per 100,000 individuals. These patients accounted for 16% of the primary humoral immunodeficiency groups (with selective IgA 45%, CVID 29%, and selective IgG 10%). Spain's Registry for Primary Immunodeficiency Diseases reported 1079 cases registered between January 1980 and December 1995. Of these, 49 were reported as XLA. In Brazil, of 166 cases of primary immunodeficiencies diagnosed over 15 years, 60.8% (101) were primary humoral deficiencies. Of these, XLA was the least frequent (9), compared with IgA deficiency (60) and transient hypogammaglobulinemia (14). In South Africa, antibody deficiencies predominate, accounting for 56% (52 of 93) of diagnoses, compared to Australia, where antibody deficiencies comprised 71% of 500 cases enrolled in a national registry. In Hong Kong, humoral defects were identified in 50 of 117 patients diagnosed with primary immunodeficiency.

Mortality/Morbidity: 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.

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.

History: History is similar to that for Bruton agammaglobulinemia because the patient is unable to produce functional humoral immunity. Patients may have problems with recurrent upper and/or lower respiratory tract infections or with chronic diarrhea. However, patients with mutations in the m heavy chain and non-Btk mutations tend to develop symptoms earlier and are more likely to have severe symptoms.

- Encapsulated bacteria with Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and pseudomonal species (in that order) cause most infections. Other bacteria, such as Salmonella and Giardia species, may also cause problems. Two cases of Campylobacter coli infection (one with bacteremia and cellulitis; another with pericarditis) have also been described.

- Almost three fourths of patients with agammaglobulinemia have infections occurring in the upper respiratory tract with otitis and sinusitis. Lower respiratory tract infections (eg, pneumonia, bronchiolitis), gastrointestinal tract infections (eg, gastroenteritis), or both occur in more than two thirds of patients.
- Other bacterial infections, such as pyoderma, sepsis, meningitis, osteomyelitis, and septic arthritis occur less frequently. Lower-grade pathogens, such as Pneumocystis carinii pneumonia, have also been reported. Additionally, sites of infection may be unusual with the encapsulated pyogenic bacteria, such as H influenzae lymphadenopathy or pneumococcal meningitis.

- Although patients with agammaglobulinemia are usually able to handle viral infections, they are susceptible to certain viruses that replicate in the gastrointestinal tract and then spread to the CNS. This indicates the importance of antibody production in limiting the spread of infections by enteroviruses such as poliovirus, echovirus, and coxsackievirus.

- Patients may present with vaccine-related poliomyelitis after immunization with the live poliovirus vaccine (see Hidalgo's report). Although prolonged secretions of a virus have been described (up to 637 days after vaccination), poliovirus carriers among people with primary immune deficiency appears to be rare, based on 3 separate studies, and may not manifest with disease.

- Alternately, echovirus infection of the CNS may cause chronic encephalomyelitis or meningoencephalitis. In 13 patients with primary hypogammaglobulinemia, Rudge et al (1996) described 3 clinical pictures: (1) progressive myelopathy in 1 patient, (2) myelopathy progressing to an encephalopathy in 4 patients, and (3) pure encephalopathy in 8 patients. Enteroviral infection was found in 7 patients by either culture or polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). However, Katamura et al (2002) described a nonprogressive viral myelitis in a patient and suggested that the prognosis of CNS infections in agammaglobulinemia is not determined by the Ig level alone and that they are not always progressive or fatal.

- The use of interventricular infusion of Ig has been well-documented in these patients.

- Virus-induced autoimmune diseases such as a dermatomyositislike syndromes and chronic arthritis may also occur. These diseases suggest an element of antibody production dysregulation in their pathogenesis, although in some cases, enteroviruses have been isolated from skin or joints.

- Mycoplasma or Ureaplasma organisms may play a role in other cases of chronic arthritis. In a survey of 358 patients with primary antibody deficiency, mycoplasmal infection was the most common cause of severe chronic erosive arthritis. Patients with mild cases rapidly respond to antimicrobial therapy, such as tetracycline. In more severe cases, arthritis improved following treatment with Ig. Overall, 7-22% of agammaglobulinemia patients develop joint manifestations.

- A case of juvenile onset psoriatic arthritis has been described in a patient with agammaglobulinemia.

- The constellation of symptoms in a family of brothers with leukoencephalopathy, arthritis, colitis, and hypogammaglobulinemia prompted some to label this the LACH syndrome (Bonkowsky, 2004).

- Other associated autoimmune disorders most commonly include hematological manifestations (eg, thrombocytopenia, hemolytic anemia, neutropenia) and also alopecia totalis, glomerulonephritis, protein-losing enteropathy, malabsorption with disaccharidase deficiency, and amyloidosis.

- Other patients in whom measurements of Ig may be helpful include those with renal dialysis and patients in pediatric ICUs. In the former, IgG and IgG subclass deficiency were found in 8 out of 12 children undergoing continuous ambulatory peritoneal dialysis (Akman, 2002). Similarly, total IgG was below the normal for age in 14 of 20 patients admitted to a pediatric ICU (Rehman, 2003). However, a small number of patients was studied.

Physical: Patients with agammaglobulinemia appear to be healthy between bouts of infections. Patients usually do not fail to thrive, although chronic diarrhea, if present, could cause some dehydration and malabsorption. Any abnormal physical findings indicate presence of various infections for which patients have increased susceptibility. Concomitant short stature in a male suggests X-linked hypogammaglobulinemia with growth hormone deficiency syndrome.

- Most patients with agammaglobulinemia were recognized to have immunodeficiency during or shortly after their first hospitalization for infection. Most of the patients had a history of recurrent otitis or upper respiratory tract infection at the time of diagnosis, which when combined with the physical finding of markedly small or absent tonsils and cervical lymph nodes, should alert physicians to the diagnosis of agammaglobulinemia.

- Some patients have cutaneous manifestations representing several unique syndromes. One of these is known as WHIM syndrome, consisting of warts, hypogammaglobulinemia, infections, and myelokathexis. The gene responsible for this syndrome has been identified as a chemokine receptor CXCR4 (Gulino, 2003). The presence of warts may be unique since another individual has been described as having intestinal lymphangiectasis with hypogammaglobulinemia and lymphopenia as well as unrelenting cutaneous warts but without a history of infections (Lynn, 2004).

Causes: Genetic factors have included mutations of Btk only (accounting for 85-90% of patients with early onset agammaglobulinemia and an absence of B cells). The remaining cases in males and females are clinically similar to XLA and represent mutations affecting the IGHM, CD79AA, and IGLL1 genes involved in the composition of the pre-BCR or the BLNK gene involved in pre-BCR signal transduction. Non-XLA patients may have other defects that result in an arrest of B-cell differentiation at a pro–B-cell level (before the onset of Ig gene rearrangements) or defects in an adjacent gene to the Btk gene responsible for growth hormone production (XLA with growth hormone deficiency).

Also, certain infections and drugs may result in low or absent Ig levels.

- Genetic factors are described in the following examples:

- A female has been described with a translocation involving a new gene in chromosome 9 (LRRC8) that resulted in a block in B-cell differentiation at pro–,B- to pre–B-cell transition (Sawada, 2003). She had minor facial anomalies and congenital agammaglobulinemia and absent B cells in peripheral blood.

- Patients with mutations in the m heavy chain usually present initially when aged 4 months with pneumonia, otitis, gastroenteritis, chronic enterovirus encephalitis, and Pseudomonas aeruginosa septic shock. One 15-month-old child presented with fever, weakness, rash, and neutropenia 2 weeks after an oral poliovirus vaccine.

- One newborn girl with mutation in the Ig-a gene developed recurrent diarrhea and failure to thrive in the first month of life. By age 1 year, she had chronic bronchitis.

- One infant boy with mutation in the l light chain had recurrent otitis media at age 2 months. At age 3 years, he had H influenzae meningitis with arthritis.

- One boy with a BLNK defect presented with overwhelming sepsis during childhood. With IVIG treatment, he has survived to adulthood without any growth or developmental delay.

- Other patients have been described with reduced pro-B cells but no identifiable molecular defect. One was a 4-month-old infant girl with failure to thrive, recurrent otitis, candidiasis, H influenzae arthritis, and herpes simplex stomatitis. Another girl had microcephaly, persistent diarrhea, failure to thrive, and recurrent respiratory and gastrointestinal infections. This patient eventually developed pancytopenia with progressive bone marrow failure.

- Certain viral infectious have been shown to cause transient or permanent immune deficiency.

- Congenital rubella can cause hypogammaglobulinemia. Although infection with human immunodeficiency virus (HIV) usually causes hypergammaglobulinemia, in some reported pediatric cases, patients had hypogammaglobulinemia.

- Patients with X-linked lymphoproliferative syndrome (ie, Duncan disease, Purtilo syndrome) may develop overwhelming disease with infection by Epstein-Barr virus with subsequent agammaglobulinemia and a decrease in B cells. Therefore, any male with persistent hypogammaglobulinemia following mononucleosis should be closely monitored for X-linked lymphoproliferative disease.

- Drug-induced hypogammaglobulinemia has been described with immunosuppressive agents (eg, corticosteroids, rituximab), epilepsy medications (eg, phenytoin, carbamazepine), and antipsychotic medications (eg, chlorpromazine). Recurrent infections and reduced serum Ig levels resolved when treatment with the medication was stopped.

- Oral prednisone at a dose of at least 12.5 mg/d for patients with asthma has been shown to be able to result in hypogammaglobulinemia (Kawano, 2002). Hypogammaglobulinemia is also frequently seen in steroid-sensitive nephrotic syndrome. Therefore, in patients with autoimmune diseases such as systemic lupus erythematosus who are being treated with prednisone and other immunosuppressive medications, the hypogammaglobulinemia could be due to either medication use or could reflect the underlying autoimmune process.

- Some have speculated on the association between anticonvulsant hypersensitivity syndrome (a life-threatening, drug-induced, multiorgan system reaction) with herpesvirus reactivation and hypogammaglobulinemia.

- Speculation that phenytoin-induced suppressor T-cell activity and subsequent antibody deficiency has found some support with in vitro experiments.

- Malignancies such as leukemias, multiple myeloma, and neuroblastoma may have an associated hypogammaglobulinemia.

- Excessive protein loss from the gastrointestinal tract may result in hypogammaglobulinemia; however, primary antibody deficiency may also cause chronic diarrhea. Therefore, any protein-losing enteropathy should be considered in patients presenting with hypogammaglobulinemia. In these situations, specific antibody responses are intact, and circulating B cells are normal. On the other hand, gastrointestinal protein loss may also occur from lymphatic obstruction in diseases such as intestinal lymphangiectasia. Concomitant loss of lymphocytes into the intestinal tract may result in lymphopenia.

- Similarly, patients with chylothorax will also have hypogammaglobulinemia (IgG=179+/-35 mg/dL) and lymphopenia (985+/-636 cells/mL) (Orange, 2003).

Article from: eMedicine