X-linked agammaglobulinemia

Other Names: Bruton type agammaglobulinemia; Bruton's agammaglobulinemia; XLA; Agammaglobulinemia, BTK; Agammaglobulinemia, Bruton tyrosine kinase; BTK-deficiency

X-linked agammaglobulinema is a primary immunodeficiency characterized by very low levels of immunoglobulins (proteins made by the immune system to help fight infections). People affected by this condition generally begin developing frequent and recurrent bacterial infections from about 6 months of age. Commonly diagnosed infections include lung infections (pneumonia and bronchitis), middle ear infections, conjunctivitis, sinus infections, various skin infections, and infections that are associated with chronic diarrhea.

People with XLA have very few B cells, which are specialized white blood cells that help protect the body against infection. B cells can mature into the cells that produce special proteins called antibodies or immunoglobulins. Antibodies attach to specific foreign particles and germs, marking them for destruction. Individuals with XLA are more susceptible to infections because their body makes very few antibodies.

Children with XLA are usually healthy for the first 1 or 2 months of life because they are protected by antibodies acquired before birth from their mother. After this time, the maternal antibodies are cleared from the body, and the affected child begins to develop recurrent infections. In children with XLA, infections generally take longer to get better and then they come back again, even with antibiotic medications.

People with XLA can develop severe, life-threatening bacterial infections; however, affected individuals are not particularly vulnerable to infections caused by viruses. With treatment to replace antibodies, infections can usually be prevented, improving the quality of life for people with XLA.

Furthermore, children with XLA should not be given live viral vaccines. For example, they should be given inactivated polio vaccine (IPV) rather than the oral polio vaccine. The siblings of children with XLA should also be given inactivated polio vaccine (IPV) rather than oral polio vaccine in order to avoid infecting their affected sibling with live virus.

Epidemiology

XLA occurs in approximately 1 in 200,000 newborns.

Cause

Mutations in the BTK gene cause XLA. This gene provides instructions for making the BTK protein, which is important for the development of B cells and normal functioning of the immune system. Most mutations in the BTK gene prevent the production of any BTK protein. The absence of functional BTK protein blocks B cell development and leads to a lack of antibodies. Without antibodies, the immune system cannot properly respond to foreign invaders and prevent infection.

Inheritance

X-linked recessive inheritance

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. About half of affected individuals do not have a family history of XLA. In most of these cases, the affected person's mother is a carrier of one altered BTK gene. Carriers do not have the immune system abnormalities associated with XLA, but they can pass the altered gene to their children. In other cases, the mother is not a carrier and the affected individual has a new mutation in the BTK gene.

Symptoms

Affected infants are usually healthy for the first few months of life until they begin to develop recurrent bacterial infections. The most common bacterial infections are ear infections, pneumonia, pink eye, sinus infections, and infections that cause chronic diarrhea. These bacterial infections can be severe and life-threatening. Most affected individuals are not vulnerable to infections caused by viruses. Infections can usually be prevented with proper treatment.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the tonsils
• Agammaglobulinemia
• Chronic diarrhea
• Chronic otitis media(Chronic infections of the middle ear)
• Conjunctivitis(Pink eye)
• Failure to thrive(Faltering weight)
• Fatigue(Tired)
• Fever
• Glossoptosis(Retraction of the tongue)
• Immunodeficiency(Decreased immune function)
• Recurrent cutaneous abscess formation
• Recurrent pneumonia
• Short stature(Decreased body height)
• Sinusitis(Sinus inflammation)
• Skin rash
• Skin ulcer(Open skin sore)

30%-79% of people have these symptoms

• Arthritis(Joint inflammation)
• Cellulitis(Bacterial infection of skin)
• Hypocalcemia(Low blood calcium levels)
• Meningitis
• Neutropenia(Low blood neutrophil count)
• Sensorineural hearing impairment
• Sepsis(Infection in blood stream)

5%-29% of people have these symptoms

• Alopecia(Hair loss)
• Anemia(Low number of red blood cells or hemoglobin)
• Autoimmunity(Autoimmune disease)
• Hepatitis(Liver inflammation)
• Hypopigmented skin patches(Patchy loss of skin color)
• Malabsorption(Intestinal malabsorption)
• Neoplasm
• Osteomyelitis(Bone infection)
• Thrombocytopenia(Low platelet count)
• Weight loss

Diagnosis

XLA diagnosis usually begins due to a history of recurrent infections, mostly in the respiratory tract, through childhood. This is due to humoral immunodeficiency. The disorder is confirmed by blood tests that measure levels of immunoglobulins.

Tests include:

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

When XLA is suspected, it is possible to do a Western Blot test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy.

Antibody titers to vaccine antigens. Individuals with XLA fail to make antibodies to vaccine antigens like tetanus, H influenzae, or S pneumoniae.

Treatment

Treatment aims to boost the immune system, which may be accomplished by administering immunoglobulins through a vein (IVIG) or subcutaneously (SCIG). Frequent infections are generally treated with antibiotics.

Preventing bacterial infections is very important for people with XLA. Gammaglobulin (a type of protein in the blood that contains antibodies to prevent or fight infections) is the main treatment for people with XLA. In the past, most people received this by intravenous (IV) infusion every two to four weeks. However, in the last few years, an increasing number of people have been receiving it by weekly subcutaneous injections. Sometimes, people with XLA have a reaction to gammaglobulin, which may include headaches, chills, backache, or nausea. Some centers use chronic prophylactic antibiotics (continuous use of antibiotics) to prevent bacterial infections.

NIH genetic and rare disease info

• NIH info on X-linked agammaglobulinemia

X-linked agammaglobulinemia is a rare disease.

X-linked agammaglobulinemia Resources
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