X-linked Agammaglobulinemia

X-linked Agammaglobulinemia

What is X-linked agammaglobulinemia?

X-linked agammaglobulinemia, also called Bruton's agammaglobulinemia or congenital agammaglobulinemia, was the first immunodeficiency disease ever identified. "X-linked" means that the gene which causes this agammaglobulinemia is located on the X chromosome, and therefore primarily affects males because it is unlikely that females will have two altered copies of the gene. The disease causes the child to be unable to produce antibodies that make up gamma globulins in the plasma portion of blood. Antibodies are the body's primary defense against microorganisms (bacteria, viruses). In X-linked agammaglobulinemia, there is a failure of pre-B-lymphocytes to mature into B-lymphocytes (mature B-lymphocytes produce antibodies). As a result, there are no antibodies produced, and the child's body is unable to fight off bacterial infections and some viral infections.

This relatively rare inherited disease causes affected boys to become very ill since they are prone to develop infections in the middle ear, sinuses, and lungs. The infections can also involve the bloodstream or internal organs. With new advances in treatment, most patients diagnosed and treated early are able to lead relatively normal lives, without the need for isolation from potential exposure to microorganisms. In fact, children are encouraged to lead active lives.

What causes X-linked agammaglobulinemia?

X-linked agammaglobulinemia is caused by inheriting a faulty gene located on the X chromosome. Humans normally have 46 total chromosomes, or 23 pairs in each cell of their body. The 23rd pair determines gender; females have two X chromosomes, and males have one X and one Y chromosome. Females can have a disease-causing gene on one of their X chromosomes, but not exhibit any symptoms of the disease; they are referred to as "carriers" for the condition. Males, on the other hand, only have one X chromosome. So if their X chromosome carries a disease-causing gene, then they will express symptoms of the disease. Carrier females have a 50/50 chance with each pregnancy to pass the X chromosome with the faulty gene to a child. If a daughter receives the gene, she will be a healthy carrier like the mother. However, if a son receives the gene, he will have X-linked agammaglobulinemia.

Carrier testing for females in the family is available through molecular genetic testing of the BTK gene in addition to prenatal diagnosis (amniocentesis or chorionic villus sampling) for pregnancies where the mother is a known carrier.

In some families, an X-linked pattern of inheritance is not present. This could be because of a small family size with few male children. But, in some cases, the agammaglobulinemia is the result of a new mutation on the child's X chromosome that was not inherited from the mother.

What are the symptoms of X-linked agammaglobulinemia?

The symptoms of X-linked agammaglobulinemia usually become apparent in the first 6 to 9 months of age, but can present as late as 3 to 5 years of age. The following are the most common symptoms of X-linked agammaglobulinemia. However, each child may experience symptoms differently. Symptoms may include:

  • Numerous, serious, and/or life-threatening illnesses, including, but not limited to, the following:

    • Sinusitis, rhinitis (nasal infection)

    • Pyoderma (skin infection)

    • Conjunctivitis (eye infection)

    • Osteomyelitis (bone infection)

    • Meningitis (spinal cord infection)

    • Sepsis (bloodstream infection)

    • Bronchitis (bronchial infection)

    • Pneumonia (lung infection)

  • Other infections, including, but not limited to, the following:

    • Gastrointestinal infections (resulting in diarrhea)

    • Viral infections caused by the hepatitis virus (resulting in hepatitis), poliomyelitis virus (resulting in polio), and enterovirus (ECHO virus)

  • Growth failure

  • Absence of tonsils and adenoids

  • Joint disease, primarily in the knees, similar to juvenile rheumatoid arthritis

  • Autoimmune hemolytic anemia (red blood cell breakdown)

  • Glomerulonephritis (kidney inflammation)

  • Neutropenia (decreased neutrophils in the blood)

  • Dermatomyositis (skin and muscle inflammation)

Cancers, including leukemia, lymphoma, and colon cancer, have been reported in a small percentage of older patients with X-linked agammaglobulinemia.

The symptoms of X-linked agammaglobulinemia may resemble other problems or medical conditions. Always consult your child's doctor for a diagnosis.

How is X-linked agammaglobulinemia diagnosed?

A diagnosis of X-linked agammaglobulinemia is usually made based on a complete medical history and physical examination of your child. In addition, multiple blood tests may be ordered to help confirm the diagnosis.

Treatment for X-linked agammaglobulinemia

Specific treatment for X-linked agammaglobulinemia will be determined by your child's doctor based on:

  • Your child's age, overall health, and medical history

  • Extent of the disease

  • Your child's tolerance for specific medications, procedures, or therapies

  • Expectations for the course of the disease

  • Your opinion or preference

Treatment for X-linked agammaglobulinemia may include:

  • Antibody replacement. This is done through gamma globulin therapy, IVIG (given intravenously into the bloodstream). This treatment gives patients the antibodies that they cannot make themselves, in order to protect against infections and reduce the spread of infections.

  • Prompt treatment of infections (or giving antibiotics prophylactically before an infection has occurred).

  • Avoidance of live viral vaccinations (such as the one given for measles, mumps, rubella (MMR) and chickenpox (varicella), because your child could develop the disease for which the vaccine was given.

Long-term outlook for a child with X-linked agammaglobulinemia

Without antibody replacement, these children could die at an early age from severe infections. Children who develop chronic lung disease with bronchiectasis (widening and scarring of the airways) may have a shortened lifespan, in some cases. However, those children with X-linked agammaglobulinemia who are diagnosed and treated early should be able to lead normal, active lives.