**Bruton's Disease**

## Yıldız Camcıoğlu

[71] Sartor RB, Sherman PM, Mayer EA. An update on the use and investigation of probi‐ otics in health and disease. Gut. 2913;62(5):787-96. DOI: 10.1136/gutjnl-2012-302504

216 Immunopathology and Immunomodulation

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61173

#### **Abstract**

Bruton's disease, in other terms X-linked agammaglobulinemia (XLA), is the first reported primary immunodeficiency in 1952, caused by a single genetic defect. The development of B cell is under control of signals transmitted by the B-cell antigen receptor (BCR) complex. Lyn, Syk, and Bruton's tyrosine kinase (BTK) are cytoplasmic protein tyrosine kinases. XLA is caused by mutations in the Btk gene, and Btk mutations are responsible for 85% of all antibody deficiencies. Btk mutation interrupts the B-cell development at the pre-B-cell stage, resulting in the absence of B lympho‐ cytes and plasma cells in peripheral blood and peripheral lymphoid tissues. Up till now, 380 unique mutations have been identified. Autosomal recessive forms of agammaglobulinemia also result in B-cell defects, but more severe bacterial infections are seen in XLA patients due to absolute block in early B-cell development. All serum immunoglobulin isotypes are decreased, and antibody production especially against vaccine antigens is impaired.

Most of the XLA patients have clinical signs and symptoms after 6 to 9 months of age due to diminished protective maternal antibodies transmitted through placenta. The most frequent symptoms are recurrent upper and lower respiratory tract infections, some of them may suffer from neutropenia.

These patients are susceptible to enteroviral infection, which causes chronic menin‐ goencephalitis and dermatomyositis-like syndrome. Recurrent respiratory tract infections lead to chronic lung disease and bronchiectasis. These infections may disable the patient and result in death. B-cell dysfunction may also cause autoim‐ munity and B-cell malignancies.

Patients with recurrent infections have to be evaluated for the primary immunodefi‐ ciency. X-linked agammaglobulinemia has to be considered with low serum IgG, IgA, and IgM levels and severely decreased B-cell number in the peripheral blood by

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

lymphocyte subset analysis. A definitive diagnosis can be made by genetic studies. The majority of patients are diagnosed at the age of 5 years.

Immunoglobulin replacement therapy and antibiotic for infections are current choice of treatment to prevent life-threatening infections and organ damage. Hematopoietic stem cell (HSC)-based gene therapy can be curative.

Neonatal screening assays (KRECs) have been developed to determine the absence of B cells, seen in XLA.

**Keywords:** Absence of B cells, Bruton's disease, X-linked agammaglobulinemia, agammaglobulinemia, *Btk* gene mutation, Bruton's tyrosine kinase defect

#### **1. Introduction**

Bruton's disease is an X-linked agammaglobulinemia (XLA OMIM No. 300300) that was first described as primary immunodeficiency in 1952 by Dr. Bruton. It is the best-known antibody deficiency [1–5]. More than half of the patients with Bruton's diseases characterized by recurrent bacterial infections such as otitis, sinusitis, and sinopulmonary infections are developing after 7 to 9 months of age when transplacental maternal immunoglobulin G (IgG) levels decrease below protective levels in infants. In this disorder, genetic abnormalities lead to blockage in the maturation of B cells in the bone marrow and only confined to the B-cell lineage. *Streptococcus pneumoniae* and *Haemophilus influenzae* are the most common responsible encapsulated pathogens for recurrence of otitis and sinusitis. Pneumonia, empyema, menin‐ gitis, septicemia, and septic arthritis are severe infections, which may be the first warning signs of disease for physician to suspect immunodeficiency. The distinctive clinical features of the disease are early onset bacterial infections, absent mature B cells or remarkably reduced circulating B cells, severe reduction in the basal serum immunoglobulins, inability to produce antibodies against antigens, and occurrence of autoimmune diseases paradoxically. Based on these principal findings, approximately 90% of male patients presumed with XLA are likely to have mutation in *Btk* [6–9].

#### **2. History**

In 1952, an American pediatrician, Dr. Ogden Carr Bruton, described the clinical case of an 8 year-old boy who had recurrent episodes of pneumococcal sepsis [1, 2]. Dr. Bruton vaccinated the patient to prevent infections, but the boy did not produce antibodies to *Pneumococcus.* Electophoretic analysis revealed a lack of gammaglobulins in the patient's serum. Dr. Bruton treated this patient with monthly injections of exogenous gamma globulin. The patient remained free of sepsis episodes for 14 months during which he received injections. The disorder was observed only in male patients. Based on the observation of five additional male patients similar to Bruton's disease by Janeway and colleagues, the disorder later became known as X-linked agammaglobulinemia [9, 10, 11]. This disease was named Bruton's X-linked agammaglobulinemia after having discovered the first immunodeficient patient [12].

## **3. Prevalence**

lymphocyte subset analysis. A definitive diagnosis can be made by genetic studies.

Immunoglobulin replacement therapy and antibiotic for infections are current choice of treatment to prevent life-threatening infections and organ damage. Hematopoietic

Neonatal screening assays (KRECs) have been developed to determine the absence of

**Keywords:** Absence of B cells, Bruton's disease, X-linked agammaglobulinemia,

Bruton's disease is an X-linked agammaglobulinemia (XLA OMIM No. 300300) that was first described as primary immunodeficiency in 1952 by Dr. Bruton. It is the best-known antibody deficiency [1–5]. More than half of the patients with Bruton's diseases characterized by recurrent bacterial infections such as otitis, sinusitis, and sinopulmonary infections are developing after 7 to 9 months of age when transplacental maternal immunoglobulin G (IgG) levels decrease below protective levels in infants. In this disorder, genetic abnormalities lead to blockage in the maturation of B cells in the bone marrow and only confined to the B-cell lineage. *Streptococcus pneumoniae* and *Haemophilus influenzae* are the most common responsible encapsulated pathogens for recurrence of otitis and sinusitis. Pneumonia, empyema, menin‐ gitis, septicemia, and septic arthritis are severe infections, which may be the first warning signs of disease for physician to suspect immunodeficiency. The distinctive clinical features of the disease are early onset bacterial infections, absent mature B cells or remarkably reduced circulating B cells, severe reduction in the basal serum immunoglobulins, inability to produce antibodies against antigens, and occurrence of autoimmune diseases paradoxically. Based on these principal findings, approximately 90% of male patients presumed with XLA are likely

In 1952, an American pediatrician, Dr. Ogden Carr Bruton, described the clinical case of an 8 year-old boy who had recurrent episodes of pneumococcal sepsis [1, 2]. Dr. Bruton vaccinated the patient to prevent infections, but the boy did not produce antibodies to *Pneumococcus.* Electophoretic analysis revealed a lack of gammaglobulins in the patient's serum. Dr. Bruton treated this patient with monthly injections of exogenous gamma globulin. The patient remained free of sepsis episodes for 14 months during which he received injections. The disorder was observed only in male patients. Based on the observation of five additional male

agammaglobulinemia, *Btk* gene mutation, Bruton's tyrosine kinase defect

The majority of patients are diagnosed at the age of 5 years.

stem cell (HSC)-based gene therapy can be curative.

B cells, seen in XLA.

218 Immunopathology and Immunomodulation

**1. Introduction**

to have mutation in *Btk* [6–9].

**2. History**

The frequency of Bruton's disease has been estimated as 1 per 200,000 live births. Prevalence is approximately 1 per 10,000. The prevalence of XLA varies in different countries obtained from published reports. Based on national registries, the prevalence was ranging between 0.09 and 11.25 per 100,000 population [13–17]. The minimum prevalence has been reported as 0.09 (minimum) from Germany [14], while it has been reported as 11.25 (maximum) in the USA [16]. The prevalence of XLA in Eastern and Central European (ECE) countries (total population, 145,530,870) was found to be 1 per 1,399,000 individuals.
