eMedicine Specialties > Dermatology > Allergy & Immunology

Bruton Agammaglobulinemia

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Franklin Desposito, MD, Professor of Pediatrics and Clinical Director, Center for Human and Molecular Genetics, UMDNJ-New Jersey Medical School; Consulting Staff, Department of Pediatrics, UMDNJ-University Hospital
Contributor Information and Disclosures

Updated: Jun 12, 2009

Introduction

Background

X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is an inherited immunodeficiency disease caused by mutations in the gene coding for Bruton tyrosine kinase (BTK). The disease was first elucidated by Bruton in 1952, for whom the gene is named. BTK is critical to the maturation of pre–B cells to differentiating mature B cells. The BTK gene defect has been mapped to the long arm of the X chromosome at band Xq21.3 to Xq22, spanning 37.5kb with 19 exons forming 659 amino acids to complete the BTK cytosolic tyrosine kinase. A database of BTK mutations (BTKbase: Mutation registry for X-linked agammaglobulinemia) lists 544 mutation entries from 471 unrelated families showing 341 unique molecular events. No single mutation accounts for more than 3% of mutations in patients. In addition to mutations, a number of variants or polymorphisms have been found.

eMedicine Pediatrics article, Bruton Agammaglobulinemia, also may be of interest.

Pathophysiology

In the absence of BTK, B lymphocytes do not differentiate or mature. Without mature B lymphocytes, antibody-producing plasma cells are also absent. As a consequence, the reticuloendothelial and lymphoid organs in which these cells proliferate, differentiate, and are stored are poorly developed. The spleen, the tonsils, the adenoids, the Peyer patches in the intestines, and the peripheral lymph nodes may all be reduced in size or absent in individuals with X-linked agammaglobulinemia (XLA).

The protooncogene encoding for BTK has been cloned and its genomic organization determined, allowing an in-depth analysis of the role of BTK and other signaling molecules in B-cell differentiation.¹

Mutations in each of the 5 domains of BTK can lead to disease. The single most common genetic event is a missense mutation. Most mutations lead to truncation of the BTK enzyme. These mutations affect critical residues in the cytoplasmic BTK protein and are highly variable and uniformly dispersed throughout the molecule. Nevertheless, the severity of disease cannot be predicted by the specific mutations. Approximately one third of point mutations affect CGG sites, which usually code for arginine residues. The putative structural implications of all of the missense mutations are provided in the database.^2,3,4,5

BTK is necessary for the proliferation and the differentiation of B lymphocytes.^6,7,8 Males with XLA have a total or almost total absence of B lymphocytes and plasma cells. XLA is an inherited disease that occurs in approximately 1 in 250,000 males. Female carriers have no clinical manifestations. Infections begin once transferred maternal immunoglobulin G (IgG) antibodies have been catabolized, typically at about 6 months of age.

Diagnosis

Early detection and diagnosis is essential to prevent early morbidity and mortality from systemic and pulmonary infections. The diagnosis is confirmed by abnormally low or absent numbers of mature B lymphocytes, as well as low or absent expression of the µ heavy chain on the surface of the lymphocyte. Conversely, T-lymphocyte levels are elevated. The definitive determinant of XLA is the complete absence of BTK ribonucleic acid (RNA) or protein. Specific molecular analysis is made by single-strand confirmation polymorphism (SSCP), direct DNA analysis, denaturing gradient gel electrophoresis, or reverse transcriptase–polymerase chain reaction to search for the BTK mutation. SSCP is also used for prenatal evaluation, which can be performed via chorionic villus sampling or amniocentesis when a mother is known to be a carrier. IgG levels less than 100 mg/dL support the diagnosis.

Rarely, the diagnosis is made in adults in their second decade of life. This is thought to be due to a mutation in the protein, rather than a complete absence.

Frequency

United States

The estimated frequency of X-linked agammaglobulinemia (XLA) is approximately 1 case per 250,000 population. Two thirds of cases are familial, and one third of cases are believed to arise from new mutations.

International

The incidence of XLA around the world does not vary significantly.

Mortality/Morbidity

Most men with X-linked agammaglobulinemia (XLA) live into their 40s. The prognosis is better if treatment is started early, ideally if intravenous immunoglobulin G (IVIG) is started before the individual is aged 5 years. Even with treatment, patients can expect to have chronic pulmonary infections, skin disease, inflammatory bowel disease (ulcerative colitis and Crohn disease), and central nervous system complications due to enteroviral infection.

Race

Most studies involve Northern European patients. However, no racial predilection for XLA has been established.

Sex

Bruton agammaglobulinemia is an X-linked disease, with only male offspring being affected. Most cases are inherited, but, rarely, the disease manifests as a consequence of a spontaneous mutation. Mutations in the gene for the heavy mu gene (IGHM), the immunoglobulin-alpha gene, and the lambda-5 gene can cause agammaglobulinemia, with less than 1% CD19 expression on B cells. No female carriers present with the clinical manifestations of the BTK mutation.

Age

Male infants become affected by X-linked agammaglobulinemia (XLA) when maternal antibodies decline usually after age 4-6 months. If the mother has been identified as a carrier for the disease, chorionic villi sampling or amniocentesis can be performed to collect fetal lymphocytes in utero. At birth, cord blood samples can be tested for a decrease in CD19⁺ B cells and for an increase in mature T cells via fluorocytometric analysis. Children typically clinically manifest the disease at age 3-9 months with pneumonia, otitis media, cellulitis, meningitis, osteomyelitis, diarrhea, or sepsis. Rare cases of adults in their second decade have been diagnosed with a milder form XLA thought to be due to a mutation rather than an absence of the protein.

Clinical

History

Recurrent infections begin in infancy and persist throughout adulthood.

The most common presentation of X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is increased susceptibility to encapsulated pyogenic bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas species. Skin infections in patients with XLA are mostly caused by group A streptococci and Staphylococcus aureus, and they can present as impetigo, cellulitis, abscesses, or furuncles.

A form of eczema that resembles atopic dermatitis may be evident, along with an increased incidence of pyoderma gangrenosum, vitiligo, alopecia totalis, and Stevens-Johnson syndrome (from increased use of medications). Other infections that commonly present with XLA include enteroviral infections, sepsis, meningitis, and bacterial diarrhea (often caused by common organisms, such as Campylobacter jejuni and Giardia species). Individuals who are affected may have an increased incidence of autoimmune diseases leading to thrombocytopenia, neutropenia, hemolytic anemia, and rheumatoid arthritis.⁹ Persistent enteroviral infections may rarely lead to fatal encephalitis or a dermatomyositis-meningoencephalitis syndrome.¹⁰ In addition to the neurologic changes, clinical manifestations of this syndrome include edema, muscle wasting, and an erythematous rash over the extensor surfaces of the joints.

• Males affected with XLA usually present when they are younger than 1 year with unusually severe and/or recurrent otitis media, sinopulmonary infections, and pneumonia. The most common pathogen is S pneumoniae, followed by H influenzae type b, staphylococcal species, Neisseria meningitidis, and Moraxella catarrhalis. Clinical suspicion of XLA should be followed up with a detailed family history. One third to one half of all patients with XLA have spontaneous mutations and no family history of immunodeficiency. Suspect disease when increased otitis media, sinusitis, chronic coughs, and pneumonias.
• For children younger than 12 years, typical infections are caused by encapsulated bacteria. Common infections in this age group are recurrent pneumonia, sinusitis, and otitis media caused by S pneumoniae and H influenzae type b that are difficult to treat.
• In adulthood, skin manifestations become more common, usually due to Staphylococcus and group A Streptococcus organisms. Otitis media is replaced by chronic sinusitis, and pulmonary disease becomes a constant recurring problem, in both the restrictive form and the obstructive form.
• Both infants and adults can have autoimmune diseases associated with XLA. Typically, these disorders include arthritis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and inflammatory bowel disease. Inflammatory bowel disease can be very difficult to control and often promotes chronic weight loss and malnutrition.
• Diarrhea is common and is caused by Giardia or Campylobacter species.
• Patients with XLA are prone to enteroviral infections, including poliovirus.
• Ureaplasma and Mycoplasma infections may be more common than in the general population, as are bladder and joint infections.

Physical

Male infants with X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, may appear physically smaller than male infants without XLA because of delayed growth and development from recurrent infections. Rarely, XLA is associated with growth hormone deficiency, leading to significantly shorter stature in males with XLA than in males without XLA of the same age.

• On examination, the lymph nodes, the tonsils, and other lymphoid tissues may be very small or absent.
• The disease is diagnosed when the male infant repeatedly becomes ill with various sinopulmonary infections, otitis media, or staphylococcal skin infections and conjunctivitis that do not respond well to antibiotic therapy. These severe infections may be associated with neutropenia.
• Diarrhea due to Giardia, C jejuni, Shigella, and Salmonella infections may be a clinical feature of XLA.

Causes

The BTK mutations underlying X-linked agammaglobulinemia (XLA) interferes with the development and the function of B lymphocytes and their progeny. The major block occurs in the development of pro–B cells to pre–B cells and then to mature lymphocytes. Patients can have pre–B cells in the marrow, but they have few, if any, functional (mature) B cells in the peripheral blood and the lymphoid tissues.

• Search for CME/CE on This Topic »

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