X-linked agammaglobulinemia: signs and symptoms, etiology, epidemiology, diagnosis, and treatment

X-linked agammaglobulinemia (XLA) is an X-linked recessive genetic disorder that is a primary immunodeficiency disease

First, the general overview

Gamma-free globulinemia is a group of inherited immunodeficiency characterized by low

Types of gamma-absent globulinemia include X-linked agamma-no-gamma globulinemia (XLA), more rarely X-linked agamma-no-gamma globulinemia with growth hormone deficiency (about 10 reported), and autosomal recessive hereditary agammaglobulinemia (ARAG

2.

The main symptom of agammaglobulinemia is a series of bacterial infections

Infection with almost any enterovirus family and poliovirus can lead to unusually severe illness

Infections caused by mycoplasma bacteria can lead to severe arthritis, including joint swelling and pain

Men with X-linked agamma-absent globulinemia have very low

Only about 10 people in 5 or 6 households have been diagnosed with X-linked agamma-absent globulinemia with growth hormone deficiency

Autosomal recessive agambulinemia has been reported to be caused

In addition, children with XLA are prone to complications such as otitis media, chronic sinusitis, malnutrition, anemia, granulocytopenia, thrombocytopenia, growth hormone deficiency, and thyroid hormone disorders

3.

X-linked agammaglobulinemia (B lymphocyte defect) is inherited

Genetic disorders are determined by a combination of genes for specific traits on the chromosomes of the father and mother

X-linked genetic disorders are diseases caused by abnormal genes on the X chromosome and occur mainly in men

Men with X-linked disease pass on the disease genes to all of their daughters

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene of the same trait, each from one parent
.
If a person receives a normal gene and a disease gene, that person will become a carrier of the disease, but usually will not develop symptoms
.
Per pregnancy, the risk of both carrier parents passing a defective gene and having an affected child is 25%.

The risk of giving birth to a child who is a carrier like a parent is 50%
per pregnancy.
A child has a 25%
chance of getting a normal gene from both parents and inheriting it normally on that particular trait.
Men and women are at the same
risk.

All individuals carry 4-5 abnormal genes
.
Parents of close relatives (close relatives) are more likely than unrelated parents to carry the same abnormal genes, which increases the risk
of children with recessive genetic disorders.

4.
Epidemiology

Primary gamma-ananglobulinemia is a rare disease that occurs almost exclusively in men, although some women are affected
by certain types of the disease.

Data from the U.
S.
XLA Patient Registry show approximately 1 in 379 000 live births (1 in 190,000 men).

There are currently no relevant data
on the incidence and prevalence of XLA in China.

5.
Differential diagnosis

Symptoms of the following disorders may be similar
to those of primary agammaglobulinemia.
Comparison may be helpful in the differential diagnosis:

Common Variable Immunodeficiency (CVID) is a rare immunodeficiency disorder characterized by recurrent infections
of the lungs, sinuses, or ears.
The scope and severity of symptoms and findings associated with CVI may vary from case to case
.
In some cases, people with CVID are more likely to develop gastrointestinal infections and may be at higher
risk of certain types of cancer, such as non-Hodgkin lymphoma and stomach cancer.
In addition, some people with CVID have autoimmune diseases, such as immune thrombocytopenic purpura, which can cause abnormal bruising and bleeding
.
Symptoms of CVI usually become apparent
during the second to fourth decades of life.
CVID is thought to be caused by mutations in genes associated with the production of B cells that produce antibodies against infectious agents
.
In most cases, CVID may be caused by a combination of genetic and environmental factors, but autosomal recessive and autosomal dominant inheritance have been described in some families
.

High IgM syndrome (HIGM) is a rare primary immunodeficiency disorder commonly found as an X-linked recessive disorder
.
People with this disease have lower
levels of IgG, IgA, and IgE antibodies.
IgM antibody levels may be high or within the normal range
.
Symptoms and physical examination results usually become apparent
in the first or second year of life.
HIGM is characterized by recurrent bacterial infections
of membranes, skin, and/or other areas of the middle ear, sinuses, lungs, eyelids, and white parts of the eye.
Affected children may present with maladaptive absorption of nutrients, chronic diarrhea and failure to gain weight (stunting), as well as enlarged tonsils and/or enlarged liver and spleen (hepatosplenomegaly
).
In addition, affected individuals are predisposed to blood autoimmune diseases, such as neutropenia, in which certain levels of white blood cells are reduced
.
Because approximately 70% of reported cases of HIGM are X-linked, the vast majority of affected individuals are male
.
However, autosomal recessive and autosomal dominant forms
of the disease are also described.

Severe combined immunodeficiency (SCID) is one of the most serious primary immunodeficiency diseases
.
People with SCID have recurrent infections because neither B nor T lymphocytes have sufficient numbers, or they malfunction
.
If left untreated, the disease can lead to frequent, severe infections, growth retardation, and can be life-threatening
.
Other symptoms of the disease may include weight loss, weakness, middle ear infections, and skin infections
.

WAS-related diseases are a series of diseases that affect the immune system caused by mutations in the WAS gene
.
These conditions include Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and X-linked congenital neutropenia
.
Was gene abnormalities lead to WASP protein deficiency, which leads to a low platelet count (thrombocytopenia
).
WAS-associated disorders usually appear in infancy and are characterized by bloody diarrhea, recurrent infections, desquamation, itching, rashes (eczema), and small purple spots (petechiae)
on the skin.
The development of Pneumonis carinii pneumonia (PCP) and intracranial hemorrhage can be early, life-threatening complications
.
Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis, and kidney and liver damage
.
Affected individuals are at increased risk of developing lymphoma, especially after
exposure to the Epstein-Barr virus.
Diseases associated with WAS vary greatly, even in individuals in the same family
.

IgA deficiency is an antibody deficiency associated with agammaglobulinemia characterized by low levels of IgA in the blood while IgG and IgM levels are normal or elevated
.
IgA deficiency is the most common primary immunodeficiency
.
Other deficiencies in immunoglobulin isotopes are IgM deficiencies and IgG subclass defects
.

Complement component 3 deficiency is a rare inherited immunodeficiency characterized by recurrent respiratory tract infections, skin infections, recurrent middle ear infections, and sinusitis
.
The symptoms of this disease are very similar
to those of some without gamma globulinemia.
Other symptoms may include pneumonia, blood bacterial infections (sepsis), and/or inflammation of the meninges (meningitis
).
Other disorders may also be associated with complement component 3 deficiency, including vascular inflammation (vasculitis), arthralgia (arthralgia), and autoimmune diseases such as lupus (systemic lupus
erythematosus).

Transient hypogamma gammaglobulinemia in infancy, i.
e.
, serum IgG is low, while IgA and IgM are normal
.
The B-cell count in the peripheral blood is normal
.
Lymph node biopsy lacks mature plasma cells but has plasma cell-like lymphocytes
.
The ability to synthesize immunoglobulins is generally restored within 18 months
.

6.
Diagnosis

Based on clinical manifestations and laboratory results such as decreased serum immunoglobulins, lack of specific antibody responses, and absence of mature B cells in peripheral blood, it is not difficult to make clinical diagnosis of XLA, and the diagnosis depends on Btk genetic testing
.

1.
Clinical basis for diagnosis of XLA

(1) Male;

(2) Repeated and serious bacterial infections (respiratory tract, gastrointestinal tract, skin and other deep infections), the effect of antibiotic treatment is not good;

(3) with or without autoimmune diseases;

(4) Male patients
with or without similar manifestations of the disease in the maternal family.

2.
Laboratory diagnostic criteria for XLA The standards developed by the Pan American Immunodeficiency Working Group and the European Society of Immunology in 1999 (Table 120-1)
are currently used.

7.
Treatment

Immunoglobulin replacement therapy controls the symptoms of infection in most children with XLA, and the systemic condition improves
rapidly.
At present, there are two kinds of intravenous route (IVIG) and two subcutaneous routes (SIG), and IVIG
is mainly used in China.
The general principle of IVIG for the treatment of XLA is that early use is more effective than later use; Larger doses are better than small doses
.
If IVIG therapy is started late, the organic damage caused by the infection will be irreversible
.
The usual clinical dose is 400 to 600 mg/kg every 3 to 4 weeks
.
Serum IgG is maintained above 5 g/L, and infection is significantly reduced, but studies have shown that this concentration does not provide adequate protection, and some patients may require higher doses of IgG to control infection, and IVIG dosage should be individualized
.
Patients with XLA with clear infection should be actively treated with antibiotics, and the type and course
of antibiotics should be adjusted in a timely manner according to the results of susceptibility.
However, there is currently no consensus
on issues related to the use of prophylactic antibiotics in patients with XLA.

In addition to IVIG substitution, a variety of supportive therapies are needed, including improvements in nutritional, living and hygiene conditions, prevention of infection, appropriate physical exercise, maintenance of a good mental state, and prevention and treatment of various complications
.
For patients with a definitive diagnosis of XLA, oral polio vaccine
is contraindicated.

At present, it is believed that allogeneic hematopoietic stem cell transplantation is more risk-effective than beneficial to XLA, and gene therapy for correcting autologous hematopoietic stem cells is still under study, and clinical trials
on humans have not yet begun.

When a bacterial infection occurs, antibiotics
are prescribed to people without gamma globulinemia.
Some patients receive antibiotic therapy as a precautionary measure (prophylactic
).
All immunodeficient people should be protected from exposure to infectious diseases
as much as possible.
The use of corticosteroids or any drugs that suppress the immune system (immunosuppressants), as well as physical activities
such as rough contact sports that may damage the spleen, should be avoided as much as possible.

In immunocompromised patients with elevated IgM, there is a tendency to excessive bleeding, which is associated with abnormally low levels of circulating platelets
in the blood (thrombocytopenia).
This can complicate
any surgical procedure.

Genetic counseling
is recommended for patients without gamma globulinemia and their families.
Other treatments are symptomatic and supportive
.

8.
Rare disease information registration

If you are willing to seek constantly updated information, it is recommended that you register the patient's information here, even if you are not fully diagnosed, you can register, click to enter:

Patient Information Registry System for Rare Diseases

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