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Agammaglobulinemia - Types, Causes, Symptoms, Diagnosis, and Treatment

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Agammaglobulinemia is a rare immunodeficiency characterized by an absent or low count of B cells. This article will give some details about this condition.

Medically reviewed by

Dr. Bhaisara Baraturam Bhagrati

Published At November 4, 2022
Reviewed AtJanuary 5, 2023

What Is Agammaglobulinemia?

Agammaglobulinemia is also known as hypogammaglobulinemia. It is an inherited disorder that affects the immune system causing recurrent infections and other complications. Newborns who have inherited this disorder remain asymptomatic till the first six to nine months of their life due to maternal immunoglobulin G antibodies (IgG) in their system. After this age, young ones’ IgG levels fall below the protective level, and this can cause infectious conditions in them.

The most common type of agammaglobulinemia is X-linked agammaglobulinemia which affects almost 85% of the cases. Moreover, as the protective layer of maternal antibodies falls, many infection conditions, such as sinusitis, otitis media, and pneumonia, can occur in children. These are very common infections among agammaglobulinemia patients, and by the time the infection has been cured, another irreversible complication, bronchiectasis, has already developed. 10 to 30% of the children have developed rheumatologic symptoms. These young ones are prone to having septic arthritis caused by common bacteria and synovitis. Surprisingly, they are prone to fatal enterovirus infections such as chronic meningitis. As children are likely to develop vaccine-induced poliomyelitis, live vaccines are not used on patients with agammaglobulinemia.

What Are the Types of Agammaglobulinemia?

There are three types of agammaglobulinemia, such as:

  • X-linked agammaglobulinemia (XLA).

  • X-linked agammaglobulinemia with growth hormone deficiency (very rare).

  • Autosomal recessive agammaglobulinemia (ARAG).

What Are the Causes of Agammaglobulinemia?

All three types of agammaglobulinemia are a result of different etiological factors. They are:

  • X-linked Agammaglobulinemia (XLA): There is a gene named Bruton tyrosine kinase (BTK) located on the X-chromosome. The genetic abnormality in BTK is known to be the cause of XLA. BTK is a member of the Tec family and encodes non-receptor cytoplasmic tyrosine kinases. It plays an essential role in the maturation of pre-B cells and B-cells that form in the bone marrow of the body.

  • Growth hormone: Although it is very rare to find X-linked agammaglobulinemia with a growth hormone deficiency, some of the cases are documented with the same.

  • Autosomal Recessive Agammaglobulinemia (ARAG): There are multiple gene mutations involved in the cause of ARAG. These genes play an essential role in the formation of B- cells.

  • Drugs: The second immunodeficiency is possibly caused by drugs, such as steroids, Azathioprine, Cyclophosphamide, Leflunomide, and Rapamycin.

  • Viral Infections: Some viral infections cause secondary agammaglobulinemia. For instance, immunodeficiency like HIV (AIDS) affects CD4+T cells, which reduces the cellular immune response that results in infections and cancers.

What Are the Signs and Symptoms of Agammaglobulinemia?

The following are the signs and symptoms associated with agammaglobulinemia:

  • Bronchitis (the inflammatory condition of the lining of bronchial tubes that carries air from the lungs).

  • Chronic diarrhea.

  • Conjunctivitis (the infection of eyelids and eyeballs causing inflammation of the transparent membrane that lines them).

  • Otitis media (the middle ear infection usually seen in children rather than adults).

  • Pneumonia.

  • Sinusitis (inflammation of the tissue lining surrounding sinuses).

  • Skin infections, like rashes and abscesses.

  • Upper respiratory tract infections.

  • Asthma.

  • Bronchiectasis (a lung condition that causes severe coughing of mucus owing to scar tissue in the bronchi that carries air into the lungs).

How to Diagnose Pediatric Agammaglobulinemia?

  • Genetic Testing: If the family history suggests that family members have the same condition, the baby is at the highest risk of having agammaglobulinemia. After taking this family history, doctors immediately go with the next screening before the condition causes any more damage.

  • Screening Test: The first screening test is the evaluation of immunoglobulin. In the patients with agammaglobulinemia, all immunoglobulin are significantly at a low level or absent. On the contrary, some exceptional cases of XLA make some amount of IgM or IgG. Moreover, during the first few months of life, newborns make a small number of immunoglobulins, and this makes it difficult to distinguish them from patients with agammaglobulinemia.

  • Blood Test: If the above screening shows a low immunoglobulin level or if the doctors suggest the other symptoms to be a match with agammaglobulinemia, measuring the B-cells in peripheral blood is the next step doctors usually go for. A comparatively low B-cell count in the blood is the most reliable and highest match for the characteristics of XLA or ARA.

  • DNA Analysis: The presence or level of BTK protein mutation in the DNA demonstrates the presence of XLA. It confirms the diagnosis in the children by confirming the mutation. However, every family, in most cases, has a different kind of mutation in their DNA, but members of the same clan usually have the same mutation.

What Are the Complications Associated With Agammaglobulinemia?

There are some health-related complications related to the disorder. Such as:

  • Arthritis.

  • Chronic sinus.

  • Pulmonary disease.

  • Eczema.

  • Intestinal malabsorption syndrome.

How to Manage Agammaglobulinemia?

Even though medicine has advanced significantly in recent years, some conditions have no cure. Agammaglobulinemia is one of them. The abnormality related to genes cannot be reversed, replaced, or repaired. Also, it is very difficult to induce the maturation of B-lymphocyte precursors, plasma cells, and B-lymphocytes. However, there are some options to manage the symptoms, such as

  • Maintaining Hygiene: As the condition is associated with secondary infections, it is very important to maintain hygiene around children. Children of a certain age should be taught to wash their hands and wear a face mask while meeting visitors. Even untreated drinking water can cause life-threatening infectious conditions, so parents should only give treated water to their children.

  • Replacement of IV Immunoglobulins (IVIG): Immunoglobulin replacement therapy can be supportive in patients with agammaglobulinemia; however, the treatment can alter the quality of life of the patient. The treatment is given every three to four weeks intravenously and one to two weeks subcutaneously with regular follow-up visits. Even though this treatment can be an option for this fatal condition, it has some drawbacks. For instance, it is a very costly treatment and requires regular follow-up. Moreover, the treatment fights against most pathogens, but some of the uncommon pathogens can cause very severe conditions.

  • Hematopoietic Stem Cell Transplantation (HSCT): It is an alternate treatment for patients with agammaglobulinemia. However, it is very difficult to find a suitable donor as a match, and this makes this option a tedious one.

  • Antibiotics: In addition to IVIG therapy, the patients require aggressive antibiotic treatment for their infections. In some cases of chronic sinusitis and pulmonary infections, prolonged antibiotic therapy is recommended.

Conclusion:

Agammaglobulinemia can be very simple to diagnose in patients, but it is very difficult to manage. There is no cure for the condition; whatever management options are available, they are very expensive and come with challenges. As the condition can cause many complications, it is necessary to have an inter-specialty team of hematologists, pediatricians, oncologists, geneticists, and primary care providers. The primary goal of the treatment is always to prevent secondary infection in children.

Frequently Asked Questions

1.

How to Manage Agammaglobulinemia?

Even though medicine has advanced significantly recently, some conditions have no cure. Agammaglobulinemia is one of them. The abnormality related to genes cannot be reversed, replaced, or repaired. Also, it is very difficult to induce the maturation of B-lymphocyte precursors, plasma cells, and B-lymphocytes.

2.

What Is Agammaglobulinemia?

Agammaglobulinemia is also known as hypogammaglobulinemia. It is an inherited disorder that affects the immune system causing recurrent infections and other complications. Newborns who have inherited this disorder remain asymptomatic till the first six to nine months of their life due to maternal immunoglobulin G antibodies (IgG) in their system. After this age, young ones' IgG levels fall below the protective level, which can cause infectious conditions.

3.

What Are the Types of Agammaglobulinemia?

There are three types of agammaglobulinemia, such as.
 - X-linked agammaglobulinemia (XLA).
 - X-linked agammaglobulinemia with growth hormone deficiency (very rare).
 - Autosomal recessive agammaglobulinemia (ARAG).

4.

Is Agammaglobulinemia an Autoimmune Disease?

Some viral infections cause secondary agammaglobulinemia. For instance, immunodeficiency like HIV (AIDS) affects CD4+T cells, which reduces the cellular immune response that results in diseases and cancers. Drugs, such as steroids, Azathioprine, Cyclophosphamide, Leflunomide, and Rapamycin, possibly cause the second immunodeficiency triggers.

5.

How Is Agammaglobulinemia Inherited?

In X-linked agammaglobulinemia (XLA) there is a gene named Bruton tyrosine kinase (BTK) located on the X-chromosome. The genetic abnormality in BTK is known to be the cause of XLA. BTK is a member of the Tec family and encodes non-receptor cytoplasmic tyrosine kinases. It plays an essential role in the maturation of pre-B cells and B-cells that form in the body's bone marrow.

6.

What Are the Signs and Symptoms of Agammaglobulinemia?

The following are the signs and symptoms associated with agammaglobulinemia:
 - Bronchitis (the inflammatory condition of the lining of bronchial tubes that carries air from the lungs).
 - Chronic diarrhea.
 - Conjunctivitis (the infection of eyelids and eyeballs causing inflammation of the transparent membrane that lines them).
 - Otitis media (the middle ear infection usually seen in children rather than adults

7.

What Are the Complications Associated With Agammaglobulinemia?

There are some health-related complications related to the disorder. Such as:
 - Arthritis.
 - Chronic sinus.
 - Pulmonary disease.
 - Eczema.
 - Intestinal malabsorption syndrome.

8.

How Is Hypoglobulinemia Diagnosed?

Hypoglobulinemia is a condition in which the body has very low antibodies that help fight infections. The affected person is more likely to get infections that fail to heal fast.

9.

How Many Cases of Agammaglobulinemia Are Seen Among Children?

The most common type of agammaglobulinemia is X-linked agammaglobulinemia which affects almost 85% of the cases. Moreover, as the protective layer of maternal antibodies falls, many infection conditions, such as sinusitis, otitis media, and pneumonia, can occur in children. 10 to 30% of the children have developed rheumatologic symptoms.
Dr. Bhaisara Baraturam Bhagrati
Dr. Bhaisara Baraturam Bhagrati

Pediatrics

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