Autosomal Recessive Agammaglobulinemia/Agammaglobulinemia is a rare form of primary immune deficiency autosomal recessive inheritance disorders characterized by the absence of circulating B cells and low serum levels of all immunoglobulin classes or complete absence of B lymphocytes and complete lack of immunoglobulins. In the presence of normal T cell counts and function that are related to antibody deficiency (hypogammaglobulinemia) and is manifested in a variety of immune deficiency disorders in which the immune system is compromised. Immunoglobulins are produced by plasma cells, which themselves are the result of the development and differentiation of B cells. Any factor that impedes the development of the B cell lineage and/or the function of mature B cells may result in levels of serum immunoglobulins that are reduced (ie, hypogammaglobulinemia) or nearly absent (ie, agammaglobulinemia). Primary agammaglobulinemia is most commonly inherited as an X-linked trait, but autosomal-recessive (AR) forms also exist. This group of immune deficiencies may be the consequence of an inherited condition, an impaired immune system from a known or unknown cause, relation to autoimmune diseases, or a malignancy.
Immunoglobulin deficiencies may be referred to by many different names, as there are several variables within the separate but related immune disorders; and there are also many subgroups. Antibody deficiency, immunoglobulin deficiency, and gamma globulin deficiency are all synonyms for hypogammaglobulinemia.
Bruton agammaglobulinemia or X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disorder characterized by the absence of mature B cells, resulting in severe antibody deficiency and recurrent infections. [rx][rx][rx] It can manifest in an infant as soon as the protective effect of maternal immunoglobulins wanes at around three-six months of age.
Synonyms of Agammaglobulinemia
- autosomal recessive agammaglobulinemia
- X-linked agammaglobulinemia with growth hormone deficiency
- X-linked agammaglobulinemia (XLA)
- Bruton’s agammaglobulinemia;
- X-linked agammaglobulinemia;
- Immunosuppression – agammaglobulinemia;
- Immunodepressed – agammaglobulinemia;
- Immunosuppressed – agammaglobulinemia
Causes of Agammaglobulinemia
X- linked agammaglobulinemia is caused by a mutation in the Bruton tyrosine kinase (BTK) gene, located on the long arm of the X-chromosome. BTK is a member of the Tec family and encodes for cytoplasmic non-receptor tyrosine kinases, which are signal transduction molecules. BTK is critical in the maturation of pre-B cells to mature B cells, a process that occurs in the bone marrow.[rx] The disease has been associated with 544 mutations that include mainly missense mutations, insertions, deletions, and splice-site mutations.[rx]
Autosomal recessive agammaglobulinemia has been reported to be caused by genes that affect B cell development. Up to 15% are presumed to be autosomal recessive. The genetic cause of ARAG is much more complex as it involves other genes, mapped to loci on different chromosomes, 22q11.21 (IGLL1), 14q32.33 (IGHM), and 9q34.13 (LCRR8).
Beyond the primary hypogammaglobulinemia, a secondary immunodeficiency may be caused by drugs or other viral infections that affect the function of both T and B lymphocytes. Those drugs include steroids, azathioprine, cyclosporin, cyclophosphamide, leflunomide, methotrexate, mycophenolate, rapamycin, and tacrolimus. One such example of a viral infection that causes immunodeficiency, HIV (AIDS), mainly affects CD4+T cells, which in turn hampers cellular immune responses, resulting in opportunistic infections and cancers.[rx]
It has been reported that 85% of patients with chronic lymphocytic leukemia (CLL) were found to have developed hypogammaglobulinemia along the disease course. Its incidence rate increases with the duration and advancing stages of the disease. It is, therefore, more important to monitor patients for the development of any antibody deficiencies.[rx]
Congenital rubella infections also have a profound effect on immune system development. Defects observed may be transient, and can include complete immune paralysis, and other immunoglobulin abnormalities.[rx]
Autosomal recessive agammaglobulinemia (ARA)
Common variable immunodeficiency disease (CVID)
Transient hypogammaglobulinemia of infancy (THI)
X-linked hyper IgM syndrome (Hyper-IgM)
X-linked lymphoproliferative disease (X-LPD)
Severe combined immunodeficiency disease (SCID)
Common variable immunodeficiency
Growth hormone deficiency
Pediatric atopic dermatitis
Pediatric severe combined immunodeficiency
T cell disorders
The dermatologic manifestation of vitamin A deficiency
Transient hypogammaglobulinemia of infancy
Symptoms of Agammaglobulinemia
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 influenza 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.
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
- Bronchiectasis (a disease in which the small air sacs in the lungs become damaged and enlarged)
- Asthma without a known cause
Diagnosis of Agammaglobulinemia
B cells undergo maturation, differentiation, and storage in tonsils, adenoids, intestinal Peyer’s patches, and lymph nodes. Due to mutations in B cells, these structures remain underdeveloped. However, lymph nodes can appear normal due to T cell hypertrophy.
History and Physical
Family history of immunodeficiency consistent with X-linked inheritance
To establish the extent of disease and needs of an individual diagnosed with X-linked agammaglobulinemia (XLA), the following evaluations are recommended:
A complete blood count with differential
Chemistries that include renal and liver function tests, total protein, albumin, and CRP
Quantitative serum immunoglobulins and titers to vaccine antigens as baseline measurements prior to initiation of gammaglobulin substitution therapy
Baseline chest and sinus x-rays
If the patient is able to cooperate, base line pulmonary function tests
Consultation with a clinical geneticist and/or genetic counselor
A typical diagnostic test sequence would evaluate serum levels of IgG, IgM, and IgA, the number of CD19-positive or CD20-positive B cells in circulation, humoral vaccine responses, BTK protein expression in peripheral monocytes, and Btk gene sequencing.
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.
Test results consistent with a diagnosis of XLA in a male patient with a history of recurrent bacterial infections would include finding:
Serum levels of IgG, IgM, and IgA that are more than two standard deviations below age-matched controls
Absence of mature B lymphocytes in the peripheral circulation (i.e., fewer than 1-2%)
Little or no increase in antibody titers 3-4 weeks after protein- or polysaccharide antigen vaccines (e.g., immunizing against pneumococcal pneumonia or diphtheria-tetanus)
Low or absent BTK protein or mRNA expression levels
Detection of disease-causing mutations in the Btk gene
During the early stages of life – passively transferred maternal IgG provides protection 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 influenza type B. Other less commonly reported causative bacteria were Pseudomonas, Neisseria meningitides, 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]
Marked reduction in all classes of serum immunoglobulins [Lederman & Winkelstein 1985, Conley et al 2005]
The serum IgG concentration is typically <200 mg/dL (2 g/L). Most but not all individuals with XLA do have some measurable serum IgG, usually between 100 and 200 mg/dL, and ~10% of individuals have serum concentration of IgG >200 mg/dL.
The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration is almost always associated with immunodeficiency.
Markedly reduced numbers of B lymphocytes (CD 19+ cells) in the peripheral circulation (<1%) [Conley 1985, Nonoyama et al 1998]
Antibody titers to vaccine antigens. Individuals with XLA fail to make antibodies to vaccine antigens like tetanus, H influenzae, or S pneumoniae.
Severe neutropenia in ~10%-25% of individuals at the time of diagnosis, usually in association with pseudomonas or staphylococcal sepsis [Conley & Howard 2002
Male proband. The diagnosis of XLA is established in a male proband with suggestive clinical and laboratory findings and identification of a hemizygous pathogenic variant in BTK by molecular genetic testing
Single-gene testing. Sequence analysis of BTK is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.Note: (1) Because approximately 3%-5% of individuals with a BTK pathogenic variant have large deletions that include all or part of BTK and the closely linked gene TIMM8A (also called DDP) resulting in XLA and deafness-dystonia-optic neuropathy syndrome (DDON; also called Mohr-Tranebjærg syndrome) [Richter et al 2001, Sedivá et al 2007], additional testing with chromosomal microarray analysis (CMA) may be warranted. (2) For individuals with clinical features of XLA and DDON, consider CMA testing first.
A multigene panel that includes BTK and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes BTK) fails to confirm a diagnosis in an individual with features of XLA. Such testing may also provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
X-linked agammaglobulinemia (XLA) is an inborn error of immune function that can cause life-threatening infections and chronic lung disease 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. 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 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.
Treatment of Agammaglobulinemia
There is no curative treatment for XLA. However, management is by preventing, reducing, and treating infections.[rx][rx]
The optimal management of patients with XLA includes
Regular immunoglobulin replacement therapy, using intravenous or subcutaneous infusions
Therapeutic and prophylactic use of antibiotics to treat and prevent bacterial infections
Careful monitoring to manage reactions arising from immunoglobulin infusions, complications of infections, or the emergence of clinical disease (e.g., autoimmune, inflammatory, malignant)
Support (nutritional, social, psychological, and educational)
Counseling about the importance of receiving all available immunizations except for those containing live bacteria or viruses, e.g., polio (OPV, oral polio vaccine), measles/mumps/rubella (MMR), chickenpox (Varivax), BCG, yellow fever, and rotavirus (Rota-Teq)
Intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) therapy requires several considerations:
Both IVIG and SCIG – are appropriate first-line therapies. IVIG may be preferred if a larger infusion volume due to a higher dose requirement is needed. SCIG has been reported to have a lower incidence of adverse reactions and allows for a more stable IgG trough following injection.[rx]
Most adverse reactions are transient and pose no serious threat to the patient. These include immediate effects such as headache, fever, myalgia, hypo/hypertension, nausea, and chest pain. Reactions that resemble anaphylaxis are associated with higher transfusion rates and occur during the infusion. Although IgA deficiency is associated with a risk of anaphylaxis during IVIG infusion, antibodies against IgA are unlikely in XLA patients due to agammaglobulinemia. Reactions may temporarily require cessation of the infusion until symptomatically managed with agents such as NSAIDs (for flushing, pain, and headache), diphenhydramine (for pruritus, rashes, and flushing), ondansetron (for nausea or vomiting), or muscle relaxants (for muscular spasm).
Delayed reactions are of greater concern, though less common, and include thromboembolism due to hyperviscosity, renal failure secondary to osmotic injury associated with sucrose-containing preparations, pseudo hyponatremia, autoimmune hemolytic anemia, aseptic meningitis, and neutropenia.[rx]
The primary precautionary measure against infections for these patients is hygiene-focused, such as handwashing and avoidance of respiratory droplets. If possible, these patients should avoid the ingestion of untreated drinking water.
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 of 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 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. As prophylactic therapy, many antibiotics 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.
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.
Muscle injections – of immunoglobulin (Imig) were common before IVIg was prevalent, but are less effective and much more painful; hence, IMIg is now uncommon. Subcutaneous treatment (SCIg) was recently approved by the U.S. Food and Drug Administration (FDA), which is recommended in cases of severe adverse reactions to the IVIg treatment.
Genetic counseling – is recommended for people with agammaglobulinemias and their families. Another treatment is symptomatic and supportive. 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]
It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio, or measles, mumps, rubella (MMR vaccine). Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active vaccines in general have any beneficial effect on XLA patients as they lack the normal ability to maintain immune memory.
XLA patients are specifically susceptible to viruses of the Enterovirus family, and mostly to: poliovirus, cox sackieviruscoxsackie virus (hand, foot, and mouth disease), and Echoviruses. These may cause severe central nervous system conditions as chronic encephalitis, meningitis, and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus (EBV), as they lack mature B cells (and so HLA co-receptors) needed for the viral infection.[rx] Patients with XLA are also more likely to have a history of septic arthritis.[rx]
It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE antibodies. There is no special hazard for XLA patients in dealing with pets or outdoor activities.[rx] Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses.
Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia (CVID), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood. In addition, to X-linked agammaglobulinemia, a couple of autosomal recessive agammaglobulinemia gene mutations have been described including mutations in IGHM,[rx] IGLL1, CD79A/B, BLNK [rx], and deletion of the terminal 14q32.33 chromosome.[rx]
XLA was also historically mistaken as Severe Combined Immunodeficiency (SCID), a much more severe immune deficiency (“Bubble boys”). A strain of laboratory mouse, XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene and exhibit a similar, yet milder, immune deficiency as in XLA