X-linked Agammaglobulinemia (Congenital Agammaglobulinemia, Bruton's Agammaglobulinemia

X-linked agammaglobulinemia (XLA)

Are You Confident of the Diagnosis?

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by an intrinsic defect in the maturation of pre-B-cells to B-cells and ultimately immunoglobulin-secreting plasma cells. As a result, affected patients (male) have markedly reduced serum immunoglobulin levels and nearly absent antibody levels. Since the disorder is the result of mutations in a gene on the X-chromosome that is necessary for B-cell development, it is inherited as an X-linked recessive trait.

What you should be alert for in the history

Approximately 50% of affected males have a positive family history for the disorder in either a brother, a male maternal first cousin, or a maternal uncle. Thus, the presence of a positive family history can be a very useful tool in suspecting the diagnosis.

However, 50% of affected males present without a known positive family history of the disorder, and in that setting, there are clinical signs and symptoms that are helpful. Since maternal IgG crosses the placenta, effectively replacing that which the patient cannot make for himself, these patients are usually well for the first 2 or 3 months of life until the maternal IgG has disappeared.

An increased susceptibility to infection is the clinical hallmark of the disorder. Recurrent pyogenic infections such as otitis, pneumonia, bacteremia/sepsis, meningitis, osteomyelitis/septic arthritis and skin infections are common and are usually caused by encapsulated bacteria such as Pneumococcus, streptococcus, Haemophilus influenzae, and Pseudomonas. Although these patients have also shown an increased susceptibility to parasitic infections (Giardia and Pneumocystis jiroveci) and certain viral infections (vaccine-related polio and systemic, chronic Coxsackie and ECHOvirus), bacterial infections are still the most prominent. There are specific, unusual skin infections that are characteristic of XLA (see Unusual Clinical Scenarios).

Characteristic findings on physical examination

The only characteristic physical finding is an absence of tonsillar and adenoidal tissue, areas normally rich in B-lymphocytes. However, since infants under the age of 3 to 6 months normally have small tonsils and adenoids, this characteristic physical finding may not be reliable until 6 months of age and thereafter.

Expected results of diagnostic studies

Diagnostic studies helpful in XLA reflect the underlying lack of development of B-cells. Thus, B-cells will be markedly reduced (<1%) in the blood, bone marrow and lymph nodes and plasma cells will be absent in bone marrow, lymph nodes and the lamina propria of the intestine. Serum immunoglobulins (IgG, IgA, and IgM) will be markedly reduced, and antibody function severely compromised. Identification of a mutation in the responsible gene, Bruton's Tyrosine Kinase (BTK) is the gold standard for the specific diagnosis and is especially important in genetic counseling of the patient, his parents, sisters, and maternal aunts and cousins.

Diagnosis confirmation

XLA may resemble a number of other disorders characterized by severe hypogammaglobulinemia. The most common of these is common variable immunodeficiency (CVID), a cause of hypogammaglobulinemia in which the etiology is unknown. In CVID, females may be affected, B-cells are usually present, and tonsils and adenoids may be present. Severe combined immunodeficiency can also present with severe hypogammaglobulinemia, but these patients also have a marked decrease in T-cell number and/or a severe deficiency in T-cell function.

The hyper-IgM syndrome also has marked deficiencies in IgG levels, but their level of IgM is normal or elevated. Hypogammaglobulinemia, secondary to gastrointestinal (GI) or renal loss, is associated with low serum albumin, making differential diagnosis possible. Finally, the presence of a positive family history compatible with X-linked recessive inheritance and/or molecular genetic confirmation of the mutation makes differential diagnosis possible.

Who is at Risk for Developing this Disease?

Since XLA is an X-linked recessive disease, only males are affected.

What is the Cause of the Disease?

XLA is a primary immunodeficiency characterized by an intrinsic defect in the maturation of pre-B-cells to B-cells and immunoglobulin secreting plasma cells. As a result, affected patients (male) have markedly reduced serum immunoglobulin levels and nearly absent antibody levels. Since the disorder is the result of mutations in the BTK gene on the X-chromosome that is necessary for B-cell development, it is inherited as an X-linked recessive trait.

Systemic Implications and Complications

The complications of XLA are related to the increased susceptibility to infection. If the diagnosis is not made early in life and treatment not initiated before complications of the infections develop, patients may suffer with chronic pulmonary infections and pulmonary insufficiency. Similarly, central nervous system infections, such as meningitis, may lead to neurologic sequelae and developmental issues. Finally, hearing loss secondary to chronic otitis media was relatively common in the first few decades after discovery of the disease, although less common now.

Treatment Options

The most important treatment is to replace the patient's absent immunoglobulin. There are two forms of effective IgG replacement therapy: intravenous immunoglobulin G, subcutaneous immunoglobulin G.

Optimal Therapeutic Approach for this Disease

The most important treatment is to replace the patient's absent immunoglobulin. There are two forms of effective IgG replacement therapy. Commercial preparations of immunoglobulin contain only IgG, thus there are theoretical reasons that the replacement IgG is not as good as producing our own immunoglobulin. First, it lacks IgA and thus is not as effective in mucosal immunity as the patient's own production of immunoglobulin would be. Second, it is passive immunity and offers no active response to an invading microorganism with production of high-titer specific antibody.

In addition to immunoglobulin replacement therapy, antibiotics should be used for the early treatment of bacterial infections.

Patient Management

Optimal patient management involves a number of strategies.

First and foremost is replacement immunoglobulin therapy. Whether the patient is treated with intravenous or subcutaneous IgG, the aim is to maintain his trough level (the level immediately before his next treatment) of IgG above 500mg/dL and/or an increment of 400mg above his pretreatment level. Monitoring trough IgG levels monthly in the first few months after initiating IgG replacement therapy and semi-annually thereafter can be very helpful in deciding dose and frequency of replacement therapy. Importantly, if the clinical response in terms of infection is not satisfactory, then increasing the dose of IgG may be desirable.

Antibiotics should be used early in the course of any possible bacterial infection.

Finally, the patient's family should be instructed in the way in which the disease is inherited (X-linked) and the implications of that form of inheritance on future pregnancies of his parents and on the carrier status of sisters, maternal aunts and maternal cousins. When patient reaches an appropriate age, he should be counseled as to the risk of his daughters being a carrier (100%) and his sons being affected (0%)

Unusual Clinical Scenarios to Consider in Patient Management

There are three clinical scenarios that specifically relate to the practice of dermatology.

The first is the relatively common occurrence of pyogenic skin and soft tissue infections such as impetigo, cellulitis and subcutaneous abscesses.

The second is a chronic systemic infection with Helicobacter species that most commonly involves the blood stream and skin. The skin lesions are elevated, violacious, and indurated and most commonly involve the extremities. A recent report detailed pyoderma gangrenosum-like lesions in a patient with XLA due to Helicobacter bilis that responded to tobramycin and meropenem.

Finally, chronic enteroviral infections caused by ECHO virus or Coxsackie virus were common before the introduction of intravenous/subcutaneous immunoglobulin therapy but are less common now. These infections were chronic, lasting months and years, and involved the blood stream, CNS, liver, muscle and skin. One of their clinical manifestations was a skin and muscle lesion that clinically and pathologically resembled dermatomyositis.

What is the Evidence?

Bruton, OC. "Agammaglobulinemia". Pediatrics . vol. 9. 1952. pp. 722.

(This is the first description of the disease. It is also the first description of any of the primary immunodeficiency diseases, which now number over 150. It is a beautifully written case report by a clinician.)

Tsukada, S, Saffran, DC, Rawlings, DJ, Parolini, O, Allen, RC, Klisak, I. "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia". Cell . vol. 72. 1993. pp. 279.

Vetrie, D, Vorechovosk, I, Sideras, Holland, J, Davies, A, Flinter, F. "The gene involved in X-linked agammaglobulinemia is a member of the src family of protein tyrosine kinases". Nature. vol. 361. 1993. pp. 226.

(This, and the preceding article, are the 2 articles published almost simultaneously that identified the molecular genetic basis for X-linked agammaglobulinemia. The identification of the molecular genetic basis for the disorder made it possible to identify a broader range of patients with the disorder, and therefore expanded its clinical picture. It also allowed for specific identification of carrier females and prenatal diagnosis.)

Winkelstein, JA, Marino, MK, Lederman, MM, Jones, SM, Sullivan, K, Burks, AW. "X-linked agammaglobulinemia: Report on a registry of 201 patients". Medicine. vol. 85. 2006. pp. 193.

(This article reports clinical findings in a large series of patients with XLA in a national registry. It provides detailed clinical data on the prevalence of specific infections such as skin and soft tissue infections, complications and long-term outcomes.)

Halliday, E, Winkelstein, JA, Webster, AD. "Enteroviral infections in primary immunodeficiency". J Infection. vol. 46. 2003. pp. 1.

(This review summarizes the clinical findings of systemic enteroviral infections in patients with XLA, including those patients with dermatomyositis.)

Bardelas, JA, Winkelstein, JA, Seto, DSY. "Fatal ECHO 24 infection in a a patient with hypogammaglobulinemia: Relationship to dermatomyositis-like syndrome". J Pediatr. vol. 96. 1977. pp. 396.

(This is the first documentation of enterovirus causing dermatomyositis in patients with XLA.)

Simons, E, Spacek, LA, Lederman, HM, Winkelstein, JA. "Helicobacter cinaidi bacteremia presenting as macules in an afebrile adult with X-linked agammaglobulinemia". Infection . vol. 32. 2004. pp. 367.

(This article reports a single patient with this unusual infection in XLA and reviews all the previous cases.)

Murray, PR, Jain, A, Uzel, G, Ranken, R, Ivy, C, Blyn, LB. "Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: Identification of Helicobacter bilis by mass spectrometry analysis". Arch Dermatol . vol. 146. 2010. pp. 523.

(This article describes an unusual complication of Helicobacter infection in patients with XLA.)
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