Agammaglobulinemia is an autoimmune inflammatory, a chronic disorder related to antibody deficiency (hypogammaglobulinemia), and disorders in which the immune system is compromised. 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 names, such as there are several variables within the separate but related immune disorders; and there are also many subgroups and sub type. Antibody deficiency, immunoglobulin deficiency, and gamma globulin deficiency are all synonyms for hypogammaglobulinemia.
X-linked agammaglobulinemia is a primary immunodeficiency characterized by very low levels of immunoglobulins that are naturally produced (proteins made by the immune system to help fight infections). People affected by this condition generally begin developing frequent and recurrent bacterial infections, and another micro organism from about 6 months of age. The most frequent infections include lung infections (pneumonia and bronchitis), middle ear infections, conjunctivitis, sinus infections, various skin infections, and infections that are associated with chronic diarrhea.[rx][rx][rx] X-linked agammaglobulinemia is caused by changes (mutations) in the BTK gene and is inherited in an X-linked recessive manner.[rx][rx] Treatment aims to boost the immune system and make hard immunity which may be accomplished by administering immunoglobulins through a vein (IVIG) or subcutaneously (SCIG). Frequent infections are generally treated with antibiotics.[rx][rx]
Subdivisions of Agammaglobulinemia
- autosomal recessive agammaglobulinemia
- X-linked agammaglobulinemia with growth hormone deficiency
- X-linked agammaglobulinemia (XLA)
Symptoms
The major symptoms of agammaglobulinemia are caused by serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes indicate the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of symptoms of such infections only late in the first year of childhood life, after the IgG antibodies from the mother have been depleted.
Infections by almost any group of the enterovirus family and the most common poliomyelitis virus can result in unusually severe illness in children with agammaglobulinemia. The second is 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, difficulty swallowing, posture problems, muscle spasticity, and spasm. infected areas of patchy, reddish skin may appear around the eyes, knuckles, and elbows and occasionally on the knees and ankles joint.
Infections caused by mycoplasma bacteria frequently can lead to severe arthritis including joint pain, swelling, and pain, in children with primary agammaglobulinemia. Hemophilus influenzae is also the most common mucous-producing infection (pyogenic) that occurs in people with X-linked agammaglobulinemia. Children may also have repeated infections by the bacteria pneumococci, streptococci, and staphylococci bacteria, and infrequently pseudomonas infections.
Males with an X-linked form of agammaglobulinemia have very low levels of IgA, IgG, IgE, and IgM antibodies circulating in their blood. Specialized white blood cells (neutrophils) are impaired in their ability to destroy bacteria, viruses, or other 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.
This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.
| Medical Terms | Other Names |
Learn More:
HPO ID
|
|---|---|---|
| 80%-99% of people have these symptoms | ||
| Abnormality of the tonsils | 0100765 | |
| Agammaglobulinemia | 0004432 | |
| Chronic diarrhea | 0002028 | |
| Chronic otitis media |
Chronic infections of the middle ear
|
0000389 |
| Conjunctivitis |
Pink eye
|
0000509 |
| Failure to thrive |
Faltering weight
[ more ] |
0001508 |
| Fatigue |
Tired
[ more ] |
0012378 |
| Fever | 0001945 | |
| Glossoptosis |
Retraction of the tongue
|
0000162 |
| Immunodeficiency |
Decreased immune function
|
0002721 |
| Recurrent cutaneous abscess formation | 0100838 | |
| Recurrent pneumonia | 0006532 | |
| Short stature |
Decreased body height
[ more ] |
0004322 |
| Sinusitis |
Sinus inflammation
|
0000246 |
| Skin rash | 0000988 | |
| Skin ulcer |
Open skin sore
|
0200042 |
| 30%-79% of people have these symptoms | ||
| Arthritis |
Joint inflammation
|
0001369 |
| Cellulitis |
Bacterial infection of skin
[ more ] |
0100658 |
| Hypocalcemia |
Low blood calcium levels
|
0002901 |
| Meningitis | 0001287 | |
| Neutropenia |
Low blood neutrophil count
[ more ] |
0001875 |
| Sensorineural hearing impairment | 0000407 | |
| Sepsis |
Infection in blood stream
|
0100806 |
| 5%-29% of people have these symptoms | ||
| Alopecia |
Hair loss
|
0001596 |
| Anemia |
Low number of red blood cells or hemoglobin
|
0001903 |
| Autoimmunity |
Autoimmune disease
[ more ] |
0002960 |
| Hepatitis |
Liver inflammation
|
0012115 |
| Hypopigmented skin patches |
Patchy loss of skin color
|
0001053 |
| Malabsorption |
Intestinal malabsorption
|
0002024 |
| Neoplasm | 0002664 | |
| Osteomyelitis |
Bone infection
|
0002754 |
| Thrombocytopenia |
Low platelet count
|
0001873 |
| Weight loss | 0001824 | |
| Percent of people who have these symptoms is not available through HPO | ||
| Cor pulmonale | 0001648 | |
| Delayed speech and language development |
Deficiency of speech development
[ more ] |
0000750 |
| Diarrhea |
Watery stool
|
0002014 |
| Encephalitis |
Brain inflammation
|
0002383 |
| Enteroviral dermatomyositis syndrome | 0003729 | |
| Enteroviral hepatitis | 0001412 | |
| Epididymitis | 0000031 | |
| Hearing impairment |
Deafness
[ more ] |
0000365 |
| Lymph node hypoplasia | 0002732 | |
| Otitis media |
Middle ear infection
|
0000388 |
| Pneumonia | 0002090 | |
| Prostatitis |
Inflammation of the prostate
|
0000024 |
| Pyoderma |
Pus-filled lesion
|
0000999 |
| Recurrent urinary tract infections |
Frequent urinary tract infections
Repeated bladder infections
Repeated urinary tract infections
Urinary tract infections
Urinary tract infections, recurrent
[ less ] |
0000010 |
| Septic arthritis | 0003095 | |
| X-linked recessive inheritance | 0001419 | |
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 type of mutation in the BTK gene causes X-linked agammaglobulinemia with growth hormone deficiency. The genetic cause of ARAG is the most complex involving other genes that have been mapped to 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 genes. 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.
Diagnosis
Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.
Testing Resources
- The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
Standard Therapies
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 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.
References
