AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

X-linked agammaglobulinemia (XLA) 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.

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 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.

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.

BTK is necessary for the proliferation and the differentiation of B lymphocytes. 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 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 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 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Recurrent infections begin in infancy and persist throughout adulthood.

The most common presentation of XLA 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. Persistent enteroviral infections may rarely lead to fatal encephalitis or a dermatomyositis-meningoencephalitis syndrome. 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 XLA 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 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Lymphoproliferative disorders
T-cell disorders
Transient hypogammaglobulinemia of infancy
Growth hormone deficiency
X-linked deficiency with hyper immunoglobulin M (IgM)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Perform initial studies measuring quantitative IgG, IgM, immunoglobulin E (IgE), and immunoglobulin A (IgA) levels. IgG levels should be measured first, preferably after age 6 months, when maternal levels decline. IgG levels below 100 mg/dL are usually indicative of XLA. The detection of IgG, IgA, IgM, and IgE levels is related to age. Typically, IgM and IgA are undetectable. All levels are reduced in males with XLA. Age-specific reference range values are available to compare with the patient's level.
• Once antibody levels are detected as abnormally low, confirmation is attained by using fluorocytometric analysis of B-lymphocyte and T-lymphocyte markers.
• • CD19⁺ B-cell levels lower than 100 mg/dL are diagnostic of XLA.
  • On fluorocytometric analysis, T-cell values (CD4⁺ and CD8⁺) are usually increased.
• Further analysis can be made by detecting IgG responses to T-cell–dependent and T-cell–independent antigens by administering immunizations, such as an unconjugated 23-valent pneumococcal vaccine (T-cell–independent responses) or tetanus, diphtheria, and H influenzae type b immunization (T-cell–dependent responses).

Imaging Studies

• Head radiographs may demonstrate an absence of tonsils or adenoids.
• Further imaging studies of the chest can demonstrate chronic infections or sinopulmonary diseases.

Other Tests

• Pulmonary function tests are central to monitoring lung disease, of both the obstructive type and the restrictive type. They should be checked yearly in children who can perform the test (typically age 5 y).

Procedures

• Endoscopy and colonoscopy can be used to assess the extent and the progression of inflammatory bowel disease.
• Bronchoscopy can be useful in diagnosing and tracking chronic lung disease and infections.

Histologic Findings

In patients with XLA, lymphoid tissues lack germinal centers, and plasma cells are missing from the lamina propria of the gut and from bone marrow stores. In tissue samples taken to evaluate infection, the most common finding is an intense inflammatory response.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

No curative therapy exists for XLA. Treatment for XLA is IVIG. Typical doses are 400-600 mg/kg/mo given every 3-4 weeks. Doses and intervals can be adjusted based on individual clinical responses. Therapy should begin at age 10-12 weeks. Maintenance of an IgG trough level of 500-800 mg/dL is recommended. Therapy should be started at age 10-12 weeks. Currently, no evidence supports that one particular brand or route of administration (IV vs SC) is better than the other.

• Antibiotics, such as amoxicillin and amoxicillin/clavulanate, are administered for common sinopulmonary infections. Pending culture sensitivities, intravenous ceftriaxone may be used for chronic infections, pneumonia, or sepsis. When possible, cultures must be obtained to elucidate sensitivities; many organisms will show resistance in this population. Infections with Streptococcus pneumococcus, in particular, may require ceftriaxone, cefotaxime, or vancomycin for eradication.
• Bronchodilators, steroid inhalers, and regular pulmonary function tests (at least 3-4 times a year) may be a required part of therapy in addition to antibiotics.
• Chronic dermatologic manifestations of atopic dermatitis and eczema are controlled with daily moisturizing lotions and topical steroids.
• Nutritional supplementation with multivitamins is recommended.

Surgical Care

Surgical intervention is limited to severe acute infections or unresponsive chronic infections. The most common procedures involve treating patients with recurrent otitis by inserting tympanostomy tubes and treating patients with chronic sinusitis by surgical drainage.

Consultations

Consult specialists in genetics, dermatology, gastroenterology, pulmonology, infectious diseases, and hematology.

Diet

Patients with XLA should follow their normal diet supplemented by a multivitamin. No dietary limitations are specific for XLA, although a low-fat diet may be needed for patients with inflammatory bowel disease.

Activity

Patients with XLA have no specific physical limitations. Not smoking or not being exposed to smoke is strongly recommended for patients because of the increased risk of sinopulmonary infection.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Immunoglobulins

Immunoglobulins are the mainstay of therapy. Passively supply a broad spectrum of IgG antibodies against bacterial, viral, parasitic, and mycoplasmic antigens. Check IgG levels every 3 months and then every 6 months when stable. The goal is to maintain IgG trough levels greater than 500 mg/dL in serum. Check liver function and kidney function 3-4 times a year.

Drug Category: Antibiotics

These agents treat common sinopulmonary infections (eg, pneumonia, otitis media). Drugs, such as amoxicillin and amoxicillin/clavulanate, are typical agents used. Fluoroquinolone therapy is useful for respiratory staphylococcal infections and for patients with allergies to other medications. If the infection is caused by Mycoplasma organisms, the drug of choice is clarithromycin. Severe infections may require hospitalization and IV therapy with ceftriaxone or vancomycin.

Drug Name	Ceftriaxone (Rocephin)
Description	Third-generation cephalosporin with broad-spectrum gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.
Adult Dose	Uncomplicated infections: 250 mg IM once; not to exceed 4 g Severe infections: 1-2 g IV qd or divided bid; not to exceed 4 g/d
Pediatric Dose	>7 days: 25-50 mg/kg/d IV/IM; not to exceed 125 mg/d Infants and children: 50-75 mg/kg/d IV/IM divided q12h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy; caution in breastfeeding

Drug Name	Vancomycin (Vancocin, Lyphocin, Vancoled)
Description	Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in the treatment of septicemia and skin structure infections. Indicated for patients who cannot take or in whom no response has occurred with penicillins and cephalosporins or for those who have infections with resistant staphylococci. For abdominal penetrating injuries, it is combined with an agent active against enteric flora and/or anaerobes. To avoid toxicity, current recommendation is to assay trough levels after third dose, drawn 0.5 h prior to next dosing. Use CrCl to adjust dose in patients with renal impairment. Used in conjunction with gentamicin for prophylaxis in patients allergic to penicillin undergoing GI or GU tract procedures.
Adult Dose	500 mg to 2 g/d IV divided tid/qid for 7-10 d
Pediatric Dose	40 mg/kg/d IV divided tid/qid for 7-10 d
Contraindications	Documented hypersensitivity
Interactions	Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal failure and neutropenia; red man syndrome is caused by too rapid IV infusion (dose administered over a few min) but rarely happens when dose is administered IV over 2 h or PO or IP; red man syndrome is not an allergic reaction

Drug Name	Clarithromycin (Biaxin)
Description	Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose	250-500 mg PO q12h for 7-14 d
Pediatric Dose	15 mg/kg PO divided bid
Contraindications	Documented hypersensitivity; coadministration of pimozide
Interactions	Toxicity increases with coadministration of fluconazole and pimozide; effects decrease and GI tract adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, carbamazepine, ergot alkaloids, triazolam, and HMG-CoA reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increases in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25 mL/min; administer half dose or increase dosing interval if CrCl <30 mL/min; diarrhea may be a sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Category: Bronchodilators

Bronchodilators are administered via an inhaler to reduce bronchoconstriction and inflammatory response in the lungs. Inhaled beta2-agonists, with or without steroid inhalation therapy, are the standard of care for pulmonary maintenance in XLA.

Drug Name	Salmeterol (Serevent)
Description	By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, can relieve bronchospasms. Effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at higher or more frequent doses than recommended.
Adult Dose	2 inhalations (42 mcg) bid
Pediatric Dose	<4 years: Not established 4-11 years: 1 inhalation (50 mcg) bid at least 12h apart >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; angina, tachycardia, and cardiac arrhythmias associated with tachycardia
Interactions	Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta-agonists; concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia resulting from diuretics may worsen when coadministered
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Not indicated to treat acute asthmatic symptoms

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Drug Name	Fluticasone (Flovent)
Description	Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, in turn, decreasing airway hyperresponsiveness.
Adult Dose	2 sprays (50 mcg/spray) per nostril qd; may reduce to 1 spray per nostril for maintenance; not to exceed 4 sprays (200 mcg) per day
Pediatric Dose	1 spray (50 mcg/spray) per nostril qd; may use up to 2 sprays (100 mcg) per nostril; not to exceed 4 sprays (200 mcg) per day
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, and other types of acute episodes of asthma
Interactions	Coadministration with ketoconazole may increase plasma levels but does not appear to be clinically significant
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Coughing, upper respiratory tract infection, and bronchitis may occur

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with XLA are hospitalized for severe infections or acute decompensation.

Further Outpatient Care

• Patients with XLA are treated well medically as outpatients.
• • Treatments with IVIG and necessary antibiotics for infections are all provided on an outpatient basis.
  • Most tests and evaluations can be performed and most medications can be administered on an outpatient basis.

Transfer

• Immunologists are well equipped to treat the clinical illnesses of XLA. If a patient chooses to have health care provided by a primary care physician, the physician should have a special interest and experience in immunodeficiency diseases.

Deterrence/Prevention

• Families with a known mutated gene can be prenatally evaluated to better prepare for the infant's care. Testing is performed via amniocentesis or chorionic villi sampling. After birth, testing is performed on cord blood.

Complications

• Complications for patients with XLA include chronic sinopulmonary infections, enteroviral infections of the central nervous system, increased occurrence of autoimmune diseases, and skin infections.

Prognosis

• Patients with XLA have survived into their late 40s.
• IVIG is responsible for increasing survival rates, with treatment beginning preferably before the patient is aged 5 years.
• Serious enteroviral infections and chronic pulmonary disease are often fatal in adulthood.

Patient Education

• Patients and their families must understand the nature of the disease and the importance of early treatment. Identification and treatment of common infections are necessary for a better prognosis.
• Genetic counseling is recommended for the parents and female siblings of males who are affected. Molecular characterization and carrier detection is informative in 95% of families. Prenatal diagnosis is available.
• The Immune Deficiency Foundation is a solid resource for both support and education of patients and their families. The foundation can be reached at 1-800-296-4433.
• The Jeffery Modell Foundation can be reached at 1-800-JEFF-844.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose XLA in a male with a documented family history of the disease can result in legal consequences.
• Failure to interpret relative laboratory tests, such as immunoglobulin levels or antibody responses, creates legal liability for health care providers.
• Failure of the family and medical personnel to monitor IVIG infusions is a pitfall.
• Failure of the physician to withhold all live viral vaccines is a pitfall.
• Failure of a physician to educate a patient with XLA about health care and maintenance can be a potential cause for legal action.

Special Concerns

• Special concerns for patients with XLA arise preceding surgery. In this situation, IVIG is preoperatively administered to prevent infection.
• Live vaccines must be withheld.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Amedei A, Romagnani C, Benagiano M, Azzurri A, Fomia F, Torrente F, et al. Preferential Th1 profile of T helper cell responses in X-linked (Bruton's) agammaglobulinemia. Eur J Immunol. Jun 2001;31(6):1927-34. [Medline].
• Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, Miyawaki T, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev. Feb 2005;203:216-34. [Medline].
• Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol. Oct 2000;19(2):183-204. [Medline].
• D'Eufemia P, Nigro G, Celli M, Finocchiaro R, Iannetti P, Giardini O. Low-dosage immunoglobulins for an infant with hypogammaglobulinemia, maple syrup urine disease, and parvovirus B19-associated aplastic crisis. J Pediatr Hematol Oncol. Sep-Oct 2000;22(5):485-7. [Medline].
• Eijkhout HW, van Der Meer JW, Kallenberg CG, Weening RS, van Dissel JT, Sanders LA, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. Aug 7 2001;135(3):165-74. [Medline].
• Fu JL, Shyur SD, Lin HY, Lai YC. X-linked agammaglobulinemia presenting as juvenile chronic arthritis: report of one case. Acta Paediatr Taiwan. Jul-Aug 1999;40(4):280-3. [Medline].
• Futatani T, Watanabe C, Baba Y, Tsukada S, Ochs HD. Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinaemia and carrier females. Br J Haematol. Jul 2001;114(1):141-9. [Medline].
• Galama JM, Gielen M, Weemaes CM. Enterovirus antibody titers after IVIG replacement in agammaglobulinemic children. Clin Microbiol Infect. Nov 2000;6(11):630-2. [Medline].
• Hokibara S, Agematsu K, Komiyama A. B cell development and primary immunodeficiencies with hypogammaglobulinemia. Arch Immunol Ther Exp (Warsz). 2000;48(4):267-71. [Medline].
• Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Bäckesjö CM, et al. Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. Feb 1998;101(2):276-84. [Medline].
• Islam TC, Smith CI. The cellular phenotype conditions Btk for cell survival or apoptosis signaling. Immunol Rev. Dec 2000;178:49-63. [Medline].
• Jo EK, Kanegane H, Nonoyama S, Tsukada S, Lee JH, Lim K, et al. Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase gene from seven Korean X-linked agammaglobulinemia families. J Immunol. Oct 1 2001;167(7):4038-45. [Medline].
• Kang SW, Wahl MI, Chu J, Kitaura J, Kawakami Y, Kato RM, et al. PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization. EMBO J. Oct 15 2001;20(20):5692-702. [Medline].
• Khan WN. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. Immunol Res. 2001;23(2-3):147-56. [Medline].
• LeBien TW. Fates of human B-cell precursors. Blood. Jul 1 2000;96(1):9-23. [Medline].
• Lowry WE, Huang XY. G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton's agammaglobulinemia tyrosine kinase. J Biol Chem. Jan 11 2002;277(2):1488-92. [Medline].
• Morra M, Howie D, Grande MS, Sayos J, Wang N, Wu C, et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu Rev Immunol. 2001;19:657-82. [Medline].
• Ng YS, Wardemann H, Chelnis J, Cunningham-Rundles C, Meffre E. Bruton's tyrosine kinase is essential for human B cell tolerance. J Exp Med. Oct 4 2004;200(7):927-34. [Medline].
• Nonoyama S. Recent advances in the diagnosis of X-linked agammaglobulinemia. Intern Med. Sep 1999;38(9):687-8. [Medline].
• Ohta Y, Haire RN, Litman RT, Fu SM, Nelson RP, Kratz J, et al. Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. Proc Natl Acad Sci U S A. Sep 13 1994;91(19):9062-6. [Medline].
• Pienaar S, Eley B, Beatty DW, Henderson HE. X-linked agammaglobulinaemia and the underlying genetics in two kindreds. J Paediatr Child Health. Oct 2000;36(5):453-6. [Medline].
• Quartier P, Foray S, Casanova JL, Hau-Rainsard I, Blanche S, Fischer A. Enteroviral meningoencephalitis in X-linked agammaglobulinemia: intensive immunoglobulin therapy and sequential viral detection in cerebrospinal fluid by polymerase chain reaction. Pediatr Infect Dis J. Nov 2000;19(11):1106-8. [Medline].
• Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and function: a genetic perspective. Immunol Rev. Jun 2000;175:120-7. [Medline].
• Sidhu US, Sood A, Ram S. A case of recurrent pneumonias. Indian J Chest Dis Allied Sci. Apr-Jun 2000;42(2):119-22. [Medline].
• Smith CI, Bäckesjö CM, Berglöf A, Brandén LJ, Islam T, Mattsson PT, et al. X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase. Springer Semin Immunopathol. 1998;19(4):369-81. [Medline].
• Smith CI, Islam TC, Mattsson PT, Mohamed AJ, Nore BF, Vihinen M, et al. The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. Bioessays. May 2001;23(5):436-46. [Medline].
• Speletas M, Kanariou M, Kanakoudi-Tsakalidou F, Papadopoulou-Alataki E, Arvanitidis K, Pardali E, et al. Analysis of Btk mutations in patients with X-linked agammaglobulinaemia (XLA) and determination of carrier status in normal female relatives: a nationwide study of Btk deficiency in Greece. Scand J Immunol. Sep 2001;54(3):321-7. [Medline].
• Stewart DM, Tian L, Nelson DL. A case of X-linked agammaglobulinemia diagnosed in adulthood. Clin Immunol. Apr 2001;99(1):94-9. [Medline].
• Usui K, Sasahara Y, Tazawa R, Hagiwara K, Tsukada S, Miyawaki T, et al. Recurrent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults. Respir Res. 2001;2(3):188-92. [Medline].
• Vihinen M, Kwan SP, Lester T, Ochs HD, Resnick I, Väliaho J, et al. Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia. Hum Mutat. 1999;13(4):280-5. [Medline].
• Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA). Front Biosci. Dec 1 2000;5:D917-28. [Medline].
• Wang XC, Wang Y, Kanegane H, Toshio M, Yu YH. [Gene diagnosis of X-linked agammaglobulinemia]. Zhonghua Er Ke Za Zhi. Jun 2005;43(6):449-52. [Medline].
• Wang Y, Kanegane H, Sanal O, Ersoy F, Tezcan I, Futatani T, et al. Bruton tyrosine kinase gene mutations in Turkish patients with presumed X-linked agammaglobulinemia. Hum Mutat. Oct 2001;18(4):356. [Medline].

Article Last Updated: Sep 7, 2005