What Is Agammaglobulinemia?

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Agammaglobulinemia

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.

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 and possible molecular-genetic mechanisms speculated.

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).

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.

Agammaglobulinemia is an inherited disorder in which a person has very low levels of protective immune system proteins called immunoglobulins. Immunoglobulins are a type of antibody. Low levels of these antibodies make you more likely to get infections.

Primary immunodeficiency (PI) diseases are characterized in many different ways, including:

  • Low antibody levels
  • Defects in antibodies
  • Defects in the cells and proteins of the immune system (for example, T cells, B cells, neutrophils, or the complement system)

These defects make people susceptible to recurrent infections, and other complications that may require different therapies. The most common primary immunodeficiency types result in an inability to make a very important type of protein called antibodies or immunoglobulins, which help the body fight off infections from bacteria or viruses. In addition to increased susceptibility to infection, people with PI may also have autoimmune diseases in which the immune system attacks their own cells or tissues.

Subdivisions of Agammaglobulinemia

autosomal recessive agammaglobulinemia

  • X-linked agammaglobulinemia with growth hormone deficiency
  • X-linked agammaglobulinemia (XLA)

X-linked agammaglobulinemia (XLA)

XLA is an inherited form of PI disease in which people have a mutation in the gene needed for the development of B lymphocytes, the immune cells that produce antibodies (immunoglobulins).

X-Linked Agammaglobulinemia (XLA) Symptoms

This mutation prevents the normal development of B lymphocytes, resulting in a severe deficiency in antibodies. Antibodies are an important part of the body’s immune system and provide defense against infections.

The normal development of B cells into plasma cells which produce antibodies is a stepwise process that begins with cells called stem cells, which are found in the bone marrow.

Stem cells produce immature lymphocytes (white blood cells) called pro-B lymphocytes, which develop pre-B lymphocytes. These pre-B lymphocytes form B lymphocytes, or B cells. B lymphocyte cells mature into plasma cells that produce specific immunoglobulins when they come in contact with different disease-causing substances.

One of the first types of PI to be identified, XLA is sometimes called Bruton’s agammaglobulinemia, after the man who discovered it, or congenital agammaglobulinemia, due to a patient’s inability to produce antibodies.

The mutated gene responsible for the disease is located on the X chromosome. Since XLA is an X-linked disorder, only boys are affected; however, it had been known for several years that there were girls who had an immunodeficiency that looked just like XLA. The deficiency seen in girls is Autosomal Recessive Agammaglobulinemia (ARA). The genes responsible for ARA are not located on the X chromosome but result in a deficiency similar to XLA.

Symptoms of XLA

People with XLA develop frequent infections that involve the sinuses, ears, and lungs, but may also develop infections of the bloodstream and internal organs. In addition, gastrointestinal and skin infections can be a problem.

Physical examination of most patients with XLA reveals very small tonsils and lymph nodes (glands of the neck). This is because most of the bulk of the tonsils and lymph nodes is made up of B lymphocytes. In people with XLA the absence of B lymphocytes results in the reduced size of these tissues.

Diagnosis of XLA

Diagnosis of XLA or ARA should be considered in patients with recurrent or severe bacterial infections that also have small or absent tonsils and lymph nodes.

Screening for XLA begins with a blood test that looks for the presence of immunoglobulins, because all of the immunoglobulins (IgG, IgM, and IgA) are absent or exist only in small amounts in most people with XLA.

When a doctor suspects a person has XLA, an additional blood test will test for the percentage of B cells, the immune cells not produced in XLA. A low B cell count in the blood is the most reliable indicator of XLA or ARA.

Diagnosis can be confirmed by a test that establishes the absence of a protein called Bruton’s tyrosine kinase (BTK), which is associated with XLA, or by the detection of an abnormality in the BTK gene.

Treating XLA

Only your doctor can determine which treatment is right for you and your specific health needs. Visit our Treating PI section to read about the types of PI treatment and download questions to ask your doctor.

Clinical Presentation of X-Linked Agammaglobulinemia and Autosomal Recessive Agammaglobulinemia

Patients with either XLA or ARA are prone to develop infections because they lack antibodies. The infections frequently occur at or near the surfaces of mucus membranes, such as the middle ear (otitis), sinuses (sinusitis) and lungs (pneumonia or bronchitis), but in some instances infections can involve the bloodstream or internal organs as well.

Gastrointestinal infections can also be a problem, especially those caused by the parasite, Giardia. Giardia may cause abdominal pain, diarrhea, poor growth or loss of serum proteins like gamma globulin. Some patients with agammaglobulinemia also have problems with skin infections.

In patients without antibodies, any of these infections may invade the bloodstream and spread to other organs deep within the body, such as the bones, joints or brain. Infections in XLA and ARA patients are usually caused by microorganisms that are killed or inactivated very effectively by antibodies in normal people.

The most common bacteria that cause infections are the pneumococcus, the streptococcus, the staphylococcus and Hemophilus influenzae. Some specific kinds of viruses may also cause serious infections in these patients.

The defect in B-cells is present at birth, and infections may begin at any age. However, infections often do not occur with unusual frequency until sometime between 6-18 months of age because, until then, infants are protected by antibodies acquired from the mother during the pregnancy.

On physical examination, most patients with agammaglobulinemia have very small tonsils and lymph nodes (the glands in your neck). This is because most of the bulk of tonsils and lymph nodes is made up of B-lymphocytes. In the absence of B-lymphocytes, these tissues are reduced in size.

The basic defect in both X-Linked Agammaglobulinemia and autosomal recessive agammaglobulinemia is a failure of B-lymphocyte precursors to mature into B-lymphocytes and ultimately plasma cells. Since they lack the cells that are responsible for producing immunoglobulins, these patients have severe deficiencies of all types of immunoglobulins.

Signs & Symptoms

The major symptoms of agammaglobulinemia are serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such infections only late in the first year of life, after the IgG antibodies from the mother have been depleted.

Infections by almost any of the enterovirus family and the poliomyelitis virus can result in unusually severe illness in children with agammaglobulinemia. Echovirus infection can cause a group of symptoms that closely resembles dermatomyositis. These symptoms may include muscle weakness, often in the hip and shoulder areas, and difficulty swallowing. Areas of patchy, reddish skin may appear around the eyes, knuckles and elbows and occasionally on the knees and ankles.

Infections caused by mycoplasma bacteria can lead to severe arthritis including joint swelling and pain, in children with primary agammaglobulinemia. Hemophilus influenzae is the most common mucous- producing infection (pyogenic) that occurs in people with X-linked agammaglobulinemia. Children may also have repeated infections with pneumococci, streptococci, and staphylococci bacteria, and infrequently pseudomonas infections.

Males with X-linked form of agammaglobulinemia have very low levels of IgA, IgG, and IgM antibodies circulating in their blood. Specialized white blood cells (neutrophils) are impaired in their ability to destroy bacteria, viruses, or other invading organisms (microbes).

This occurs because neutrophils require antibodies from the immune system to begin to destroy invading bacteria (opsonization). The levels of circulating neutrophils in children with agammaglobulinemia may be persistently low, or may wax and wane (cyclic, transient neutropenia) in people with these disorders. The number of B-lymphocytes in children with X-linked agammaglobulinemia is less than one one-hundredth of the normal number.

Only about 10 persons in 5 or 6 families have been diagnosed with X-linked agammaglobulinemia with growth hormone deficiency. The boys in these families have reduced or undetectable numbers of B-lymphocytes. Clinicians and geneticists speculate that a second mutation in the BTK gene, very close to the mutation in this gene that causes XLA, is responsible for the combination of agammaglobulinemia and very short stature.

Autosomal recessive agammaglobulinemia has been reported to be due to genes that affect B cell development.

Causes

X-linked agammaglobulinemia (B-lymphocyte defect) is inherited as an X-linked recessive genetic trait. The abnormal gene, named BTK, has been mapped to gene locus Xq21.3-q22. A different mutation in the BTK gene causes X-linked agammaglobulinemia with growth hormone deficiency. The genetic cause of ARAG is much more complex involving other genes that have been mapped to loci on different chromosomes: 22q11.21, 14q32.33, and 9q34.13. The genes at three sites are known as IGLL1, IGHM, and LCRR8 respectively.

Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.

Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 21q11.21” refers to band 11.21 on the long arm of chromosome 21.

Similarly 14q32.33 refers to band 32.33 on the long arm of chromosome 14, and 9q34.13 refers to band 34.13 on the long arm of chromosome 9. The site described as Xq21.3-q22 refers to a region on the long arm of the X chromosome between bands 21.3 and 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning.

It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms.

The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Definition of X-Linked Agammaglobulinemia (XLA) and Autosomal Recessive Agammaglobulinemia (ARA)

X-Linked Agammaglobulinemia (XLA) was first described in 1952 by Dr. Ogden Bruton. This disease, sometimes called Bruton’s Agammaglobulinemia or Congenital Agammaglobulinemia, was one of the first immunodeficiency diseases to be identified. XLA is an inherited immunodeficiency disease in which patients lack the ability to produce antibodies, the proteins that make up the gamma globulin or immunoglobulin fraction of blood plasma.

Antibodies are an integral part of the body’s defense mechanism against certain types of microorganisms or germs, like bacteria or viruses. Antibodies are important in the recovery from infections and protect against getting certain infections more than once. There are antibodies specifically designed to combine with each and every microbe—much like a lock and key.

Supplemental Materials

Autoimmunity and Inflammation in X-linked Agammaglobulinemia Journal of Clinical Immunology, May 2014

When a germ, such as bacteria, lands on a mucus membrane or enters the body, antibody molecules that recognize it stick to its surface. Antibody bound to the surface of a microorganism can have one or more effects that are beneficial. For example, some germs must attach to body cells before they can cause an infection and antibody prevents the germs from “sticking” to the cells.

Antibody on the surface of some microbes will also activate other body defenses (such as a group of blood proteins called serum complement) which can directly kill the bacteria or viruses. Finally, antibody coated bacteria are much easier for white blood cells (phagocytes) to ingest and kill than are bacteria which are not coated with antibody. All of these actions prevent germs from invading body tissues where they may cause serious infections. (See chapter titled “The Immune System and Primary Immunodeficiency Diseases.”)

The basic defect in XLA is an inability of the patient to produce antibodies. Antibodies are produced by specialized cells in the body, called plasma cells. Plasma cells develop in an orderly sequence of steps beginning with stem cells located in the bone marrow. The stem cells give rise to immature lymphocytes, called pro-B-lymphocytes. Pro-B-lymphocytes next develop into pre-B-cells, which then give rise to B-lymphocytes.

Each B-lymphocyte bears on its cell surface a small amount of the immunoglobulin that it is able to produce. This cell surface immunoglobulin can bind foreign substances, (an antigen). When the B-lymphocyte comes into contact with its specific antigen, like pneumococcus or tetanus, it is triggered to mature into a plasma cell which is specialized in making and secreting large amounts of that specific antibody. Each B-cell makes a slightly different antibody, or immunoglobulin, to allow the body to respond to millions of different foreign substances.

Most patients with XLA have normal numbers of B-lymphocyte precursors, but very few of these go on to become B-lymphocytes. This is the underlying defect in XLA, a failure of B-lymphocyte precursors to mature into B-cells. Patients with XLA have mutations in a gene that is necessary for the normal development of B-lymphocytes. This gene, discovered in 1993, is named Bruton’s Tyrosine Kinase (BTK) in honor of the discoverer of the disorder, Colonel Ogden Bruton, MD. As the name of the disorder suggests, the BTK gene is located on the X chromosome.

After BTK was identified as the cause of XLA, it became clear that only about 85% of children with agammaglobulinemia and absent B-cells had mutations in BTK. Since XLA is an x-linked disorder, only boys are affected; however, it had been known for several years that there were girls who had an immunodeficiency that looked just like XLA and immunologists had suggested that there were forms of agammaglobulinemia with autosomal recessive inheritance (ARA).

Since 1996, several genes that can cause ARA have been identified.

The following genes (and their official gene symbol) have been reported to cause ARA:

  • µ heavy chain (IGHM)
  • λ5 (IGLL1)
  • lgα (CD79A)
  • lgß (CD79B)
  • BLNK (BLNK)

All of these genes code for proteins that work with BTK to support the maturation of pro-B-cells into pre-B-cells. Patients with mutations in any of these genes have clinical and laboratory findings that are very similar to those seen in patients with mutations in BTK.

Clinical Presentation of X-Linked Agammaglobulinemia and Autosomal Recessive Agammaglobulinemia

Patients with either XLA or ARA are prone to develop infections because they lack antibodies. The infections frequently occur at or near the surfaces of mucus membranes, such as the middle ear (otitis), sinuses (sinusitis) and lungs (pneumonia or bronchitis), but in some instances infections can involve the bloodstream or internal organs as well.

Gastrointestinal infections can also be a problem, especially those caused by the parasite, Giardia. Giardia may cause abdominal pain, diarrhea, poor growth or loss of serum proteins like gamma globulin. Some patients with agammaglobulinemia also have problems with skin infections.

In patients without antibodies, any of these infections may invade the bloodstream and spread to other organs deep within the body, such as the bones, joints or brain. Infections in XLA and ARA patients are usually caused by microorganisms that are killed or inactivated very effectively by antibodies in normal people. The most common bacteria that cause infections are the pneumococcus, the streptococcus, the staphylococcus and Hemophilus influenzae. Some specific kinds of viruses may also cause serious infections in these patients.

The defect in B-cells is present at birth, and infections may begin at any age. However, infections often do not occur with unusual frequency until sometime between 6-18 months of age because, until then, infants are protected by antibodies acquired from the mother during the pregnancy.

On physical examination, most patients with agammaglobulinemia have very small tonsils and lymph nodes (the glands in your neck). This is because most of the bulk of tonsils and lymph nodes is made up of B-lymphocytes. In the absence of B-lymphocytes, these tissues are reduced in size.

Diagnosis of X-Linked Agammaglobulinemia and Autosomal Recessive Agammaglobulinemia

The diagnosis of agammaglobulinemia should be considered in any child with recurrent or severe bacterial infections, particularly if the patient has small or absent tonsils and lymph nodes.

The first screening test should be an evaluation of serum immunoglobulins. In most patients with agammaglobulinemia, all of the immunoglobulins (IgG, IgM and IgA) are markedly reduced or absent. However, there are exceptions; some patients with XLA make some IgM or IgG. In addition, normal babies make only small quantities of immunoglobulins in the first few months of life, making it difficult to distinguish a normal baby with a normal delay in immunoglobulin production from a baby with true immunodeficiency.

If the serum immunoglobulins are low or if the physician strongly suspects the diagnosis of agammaglobulinemia, the number of B-cells in the peripheral blood should be measured. A low percentage of B-cells (nearly absent) in the blood is the most characteristic and reliable laboratory finding in patients with either XLA or ARA.

If a newborn baby has a brother, sister, maternal cousin or maternal uncle with agammaglobulinemia, the baby is at risk to have a similar immunodeficiency and the family and physicians should immediately determine the percentage of B-cells in the blood so that treatment can be started before an affected infant gets sick.

The diagnosis of XLA can be confirmed by demonstrating the absence of BTK protein in monocytes or platelets or by the detection of a mutation in BTK in DNA. Almost every family has a different mutation in BTK; however, members of the same family usually have the same mutation. The specific gene that causes ARA can be identified by DNA analysis.

Inheritance of X-Linked Agammaglobulinemia and Autosomal Recessive Agammaglobulinemia

XLA and ARA are genetic diseases and can be inherited or passed on in a family. It is important to know the type of inheritance so the family can better understand why a child has been affected, the risk that subsequent children may be affected and the implications for other members of the family.

Now that the precise gene that causes XLA has been identified, it is possible to test the female siblings (sisters) of a patient with XLA, and other female relatives such as the child’s maternal aunts, to determine if they are carriers of the disease. Carriers of XLA have no symptoms, but they have a 50% chance of transmitting the disease to each of their sons.

In some instances, it is also possible to determine if a fetus of a carrier female will be born with XLA. Currently, these genetic tests are being performed in only a few laboratories.

Affected Populations

Primary Agammaglobulinemia is a rare disorder that occurs almost exclusively in males although some females have been affected by certain types of this disorder.

Related Disorders

Symptoms of the following disorders can be similar to those of primary agammaglobulinemias. Comparisons may be useful for a differential diagnosis:

Common Variable Immunodeficiency (CVID) is rare immunodeficiency disorder characterized by recurrent infections in the lungs, sinuses or ears. The range and severity of symptoms and findings associated with CVI may vary from case to case. In some cases, individuals with CVID have an increased tendency to develop infections of the gastrointestinal system and may have a higher risk for some types of cancer such as non-Hodgkin lymphoma and stomach cancer.

In addition, some individuals with CVID have an autoimmune disorder such as immune thrombocytopenia purpura that causes abnormal bruising and bleeding. The symptoms of CVI usually become apparent during the second to the fourth decade of life. CVID is thought to be caused by mutations in genes involved in the production of B cells that produce antibodies against infectious agents. CVID is likely to be caused by a combination of genetic and environmental factors in most cases, but autosomal recessive and autosomal dominant inheritance has been described in some families.

Hyper-IgM Syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life.

HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white portion of the eyes, the skin, and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly).

In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because approximately 70 percent of reported cases of HIGM are X-linked, the vast majority of affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described.

The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia).

WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis, kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family.

IgA deficiency is an antibody deficiency that is related to agammaglobulinemia and is characterized by low levels of IgA in the blood in the presence of normal or increased levels of IgG and IgM. IgA deficiency is the most common primary immunodeficiency. Other deficiencies of immunoglobulin isotopes are IgM deficiency and IgG subclass deficiencies.

Complement component 3 deficiency, is a rare inherited immune deficiency characterized by recurrent respiratory infections, skin infections, repeated middle ear infections, and sinusitis. The symptoms of this disorder are very similar to those of some of the agammaglobulinemia. Other symptoms may include pneumonia, bacterial infection of the blood (septicemia), and/or inflammation of the membranes that line the brain (meningitis).

Standard Therapies

The administration of intravenous gammaglobulin replacement therapy is a standard treatment for agammaglobulinemia. Intravenous gammaglobulin or subcutaneou. is used to treat agammaglobulinemias and common variable immunodeficiency.

Antibiotics are prescribed for people with agammaglobulinemia when bacterial infections occur. Some patients are treated with antibiotics as a preventive measure (prophylactically). All people who are immunodeficient should be protected as much as possible from exposure to infectious diseases. Corticosteroids or any drug that depresses the immune system (immunosuppressant drugs) should be avoided as much as possible, as well as physical activities such as rough contact sports that risk damage to the spleen.

In people with immunodeficiency with elevated IgM, there is a tendency to bleed excessively associated with abnormally low levels of circulating platelets in the blood (thrombocytopenia). This may complicate any surgical procedure.

Genetic counseling is recommended for people with agammaglobulinemias and their families. Other treatment is symptomatic and supportive.

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