Agammaglobulinemia

An agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes in the blood and lymph. Antibodies are proteins (immunoglobulins, (IgM), (IgG), etc) that are critical and key components of the immune system. They are essential if the immune system is to do its job of fighting off bacteria, viruses, and other foreign substances that threaten the body. The specialized precursor cells that produce gammaglobulins, fail to develop or function properly leading to the deficiency in the number of mature lymphocyte cells called B cells.

The agammaglobulinemia is X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia (ARAG). All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin to fight off infections.

Agammaglobulinemia is comprised of the following types:

X-linked agammaglobulinemia (XLA), was discovered in 1952 by Dr. Ogden Bruton.[rx]
X-linked agammaglobulinemia with growth hormone deficiency
Autosomal recessive agammaglobulinemia (ARAG)

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. (For more information on this disorder, choose “dermatomyositis” as your search term in the Rare Disease Database.)

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, staphylococci bacteria, and infrequently pseudomonas infections.

Males with an 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-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.

Symptoms include frequent episodes of:

Bronchitis (airway infection)
Chronic diarrhea
Conjunctivitis (eye infection)
Otitis media (middle ear infection)
Pneumonia (lung infection)
Sinusitis (sinus infection)
Skin infections
Upper respiratory tract infections

Infections typically appear in the first 4 years of life.

Other symptoms include:

Bronchiectasis (a disease in which the small air sacs in the lungs become damaged and enlarged)
Asthma without a known cause

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 is 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 of 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.

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 a 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 thrombocytopenic 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. (For more information on this disorder, choose “CVID” as your search term in the Rare Disease Database.)

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 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. (For more information on this disorder, choose “Hyper IgM” as your search term in the Rare Disease Database.)

Severe combined immunodeficiency (SCID) is the most grave of the primary immunodeficiency disorders. A person with SCID is subject to recurring infections because neither B nor T lymphocytes are present in sufficient numbers or they are malfunctioning. If untreated, this disorder may result in frequent, severe infections, and growth retardation, and can be life-threatening. Other symptoms of this disorder may include weight loss, weakness, infections of the middle ear, and skin infections. (For more information on this disorder, choose “severe combined immunodeficiency” as your search term in the Rare Disease Database.)

The WAS-related disorders are a spectrum of conditions affecting the immune system that is 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 the destruction of red blood cells (hemolytic anemia), arthritis, vasculitis, and kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to the Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family. (For more information on this disorder, choose “WAS” as your search term in the Rare Disease Database.)

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 the agammaglobulinemia. Other symptoms may include pneumonia, a bacterial infection of the blood (septicemia), and/or inflammation of the membranes that line the brain (meningitis). Other disorders may also be associated with complement component 3 deficiency including inflammation of blood vessels (vasculitis), joint pain (arthralgias), and autoimmune diseases such as lupus (systemic lupus erythematosus).

Diagnosis

The disorder is confirmed by blood tests that measure levels of immunoglobulins.

During the early stages of life, passively transferred maternal IgG protects against various infections. From 6 to 12 months of age, these antibodies start depleting, causing children with XLA to present with recurrent sino-pulmonary infections such as otitis media, sinusitis, bronchitis, and pneumonia. More than 50% of children with X-linked agammaglobulinemia have had serious infections within their first two years of life.

Pyogenic encapsulated bacteria, such as Streptococcus pneumonia and Haemophilus influenzae, are the most commonly isolated pathogens in patients with XLA. Other commonly encountered infectious organisms include Staphylococcus aureus, Pseudomonas, and Mycoplasma species. Less commonly, some patients can acquire opportunistic infections from the Pneumocystis jirovecii and other fungi.

Patients with XLA are also at higher risk of developing bloodborne bacterial infections. About 3% to 4% of patients with XLA have been reported to develop bacterial meningitis, caused predominantly by Streptococcus pneumoniae and Haemophilus influenzae type B. Other less commonly reported causative bacteria were Pseudomonas, Neisseria meningitidis, Staphylococcus aureus, Escherichia coli, and Listeria monocytogenes. Septic arthritis and osteomyelitis are other common associations reported among patients with XLA.[rx]

Patients with XLA have frequent gastrointestinal infections, and Giardia lamblia is a frequently isolated pathogen from the stool samples of these patients; it can sometimes be difficult to eradicate. Persistent infection can result in chronic diarrhea and malabsorption. Another unusual pathogen, Campylobacter jejuni, is known for causing gastrointestinal manifestations, bacteremia, and skin lesions.[rx]

The physical evaluation may reveal signs of recurrent and chronic sinopulmonary infections, which include postnasal discharge, tympanic membrane perforation, digital clubbing, and bronchiectasis. One of the greatest clinical clues in the diagnosis of XLA is absent or atrophied tonsils and lymph nodes. Some patients may also show signs of growth failure.

X-linked agammaglobulinemia (XLA) is an inborn error of immune function that can cause life-threatening infections and chronic lung diseases such as bronchiectasis. Delays in diagnosis are detrimental to the prognosis and quality of life of patients.

The diagnosis relies on clinical suspicion by history, especially family history, and physical examination followed by laboratory and genetic tests.[rx][rx]

Initial laboratory tests include:

Complete blood count with differentials
Quantitative serum immunoglobulin levels (IgG, IgA, and IgM)
Serum specific antibody titers response to immunization such as against tetanus or diphtheria

In patients with XLA, serum levels of all immunoglobulins are either low or nearly undetectable, and there will be an absent antibody response to vaccinations. If initial test results are positive, the diagnosis of XLA can be further aided by lymphocyte phenotyping using flow cytometry. The test will document an absent or reduced B-cell count and normal T-cell count. A definitive diagnosis can be made by detecting BTK gene mutation, using the Western blot technique.

Newborn screening tests have been developed for the diagnosis of XLA & other B cell defects. According to studies, immunoglobulin kappa-deleting recombination excision circles (KRECs assay), are a useful screening tool for early B cell maturation defects. Polymerase chain reactions are performed on dried blood spots to detect KRECs. KRECs are normally formed during allelic exclusion in the process of B cell maturation in normal individuals. An absence of KRECs indicates defects in B cell maturation, as in cases of XLA.[rx]

These patients have repeated sinopulmonary infections, and a variety of screening methods are used to diagnose and monitor the patient’s condition such as FEV1 (forced expiratory volume at 1 sec), FEV (forced vital capacity), and TLCO (transfer factor for carbon monoxide), as well as basic exercise tests. Imaging techniques employed include MRI and HRCT (high-resolution computerized tomography). Other tests involve sampling cultures of induced sputum and blood gas analysis. Since there is no local or national guideline for screening or treatment, the process lacks standardization, which creates a lot of variation in treatment methodologies.[rx]

In pediatric patients, clinical and laboratory tests are typically done with less frequency and are more complicated when compared to adults. For instance, infants may require sedation or a general anesthetic for imaging. And lung function testing tends to be less reliable in children under 6 years.[rx]

Due to the high risk for pulmonary infectious and non-infectious complications, these patients are often treated with broad-spectrum antibiotics before a definitive diagnosis has been made. In these situations, fiberoptic bronchoscopy (FOB) and bronchoalveolar lavage (BAL) can provide a definitive diagnosis.[rx] In addition, audiological evaluation, including audiometry, acoustic immittance assessment, and auditory brainstem-evoked response, should be an integral part of the clinical care/management of these patients.[rx]

As mentioned earlier, a variant of XLA is associated with a growth hormone deficiency; however, no current guidelines are available regarding routine monitoring of growth hormone levels in patients with XLA.

Additional Tests include:

Flow cytometry to measure circulating B lymphocytes
Immunoelectrophoresis – serum
Quantitative immunoglobulins – IgG, IgA, IgM (usually measured by nephelometry)

These other conditions include common variable immunodeficiency (CVID), transient hypogammaglobulinemia of infancy (THI), an autosomal-recessive agammaglobulinemia (ARA), and severe combined immunodeficiency (SCID). All of these conditions have low/absent B cells and their associated antibody response. However, further lab testing provides clues that support the diagnosis of XLA, such as:

A patient with SCID has a low T cell count as compared to XLA with a normal T cell count.
Generally, observations show that patients with XLA have fewer B cells than those with CVID; however, these differences are not absolute.
In THI, there is low serum IgG with or without decreased IgA and IgM levels. Children usually grow out of this, with normal immunoglobulin levels by age four. One of the proposed causes for THI is the suppressive effect of maternal antibodies (IgG) that affect fetal immunoglobulin production.

Eventually, genetic testing for the BTK gene mutation will differentiate XLA from other conditions.

Treatment

The administration of intravenous gammaglobulin replacement therapy is a standard treatment for agammaglobulinemia. Intravenous gammaglobulin or subcutaneous. 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 immunodeficient people 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.

Replacement of IV immunoglobulins (IVIG) has altered the outcome & quality of life in patients with X-linked agammaglobulinemia. Being the cornerstone of treatment, immunoglobulins are replaced every 3-4 weeks intravenously or every 1-2 weeks subcutaneously. Patients might require a loading dose (e.g., 1 dose of 1 g/kg body weight or divided into separate doses), followed by maintenance therapy (400 to 600 mg/kg/month). These doses and intervals are adjusted to maintain serum trough level at least above 500 mg/dl and may vary on a case by case basis. For instance, patients with chronic refractory sinusitis or chronic lung disease may require higher trough levels (>800 mg/dl).[rx]

Though IVIG is the main treatment option for these patients, it has its drawbacks such as;

It protects against most pathogens, but protection against uncommon pathogens is limited if the donor pool has not been exposed to them.
During treatment, only IgG is replaced while the rest of the immunoglobulins are not; these include IgA, and IgM, which have their unique functions, particularly protecting mucosal surfaces.
Replacement IVIG therapy is very costly and not sustainable – especially in areas with limited resources.

Subcutaneous administration of IgG is an alternative to IVIG in case of difficult IV access or adverse reaction to IVIG. Just as safe as IVIG, with fewer systemic adverse effects, and smaller fluctuations in serum concentrations, the ability to self-administer IgG at home brings added convenience to this method. Overall this method will improve the patient’s quality of life. In very rare cases with subcutaneous IgG, local side effects like swelling, erythema, and tenderness may occur. These side effects tend to resolve within 24 hours.[rx]

Hematopoietic stem cell transplantation (HSCT) is an alternate treatment for these patients. It is a tedious procedure with difficulty in matching suitable donors, making this treatment less popular. Additionally, there are heightened risks of allogeneic HSCT, including rejection and graft-versus-host disease. Often people in developing countries opt for HSCT because of a lack of resources and high costs, making IVIG less suitable.

A potential therapy for XLA is stem cell gene therapy, which has the potential to cure XLA. However, this technology is still in its developing stages and is associated with severe complications because of the random integration of the vector into chromosomes; this can lead to an increased risk of cancer, and in some cases, even death. While adenovirus vectors have been under investigation as a method to repair the BTK gene, the long-term success of this treatment is still unknown.[rx]

In addition to IVIG, these patients will require aggressive antibiotic therapy for any suspected or documented infections. The prolonged use of antibiotic therapy may be indicated in some patients for ongoing pulmonary infections or chronic sinusitis. In prophylactic therapy, many antibiotic options exist, but with little reliable data available, the effectiveness of a specific regimen for patients with XLA is lacking. It is typically initiated with amoxicillin, trimethoprim-sulfamethoxazole, or azithromycin. If these are deemed non-effective, others such as amoxicillin-clavulanate or clarithromycin may be used. Some practitioners opt between full therapeutic doses or half-doses, some rotate preventative antibiotics every 1 to 6 months, and others stick with one agent.

The goal of the regimen is to ensure coverage over the following organisms: Enterococcus faecalis, Staphylococcus species, Streptococcus species, Streptococcus pneumonia, and also some gram-negative bacteria like Escherichia coli, Hemophilus influenzae, Proteus mirabilis, and Neisseria gonorrhoeae.

Patients that develop bronchiectasis may benefit from bronchopulmonary hygiene, regular macrolide, and inhaled corticosteroids. The need for short- and long-acting inhaled B2 agonists, in bronchiectasis, is debatable.[rx]

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. Another treatment is symptomatic and supportive.

Agammaglobulinemia

Symptoms

Causes

Treatment

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Agammaglobulinemia

Symptoms

Causes

Related Disorders

Diagnosis

Treatment

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