X-Linked (Bruton) Agammaglobulinemia

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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 TH domain missense mutation has also been described in BTK.[1] 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. See the image below.



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Early stages of B-cell differentiation can be identified by the status of the immunoglobulin genes and by the cell surface markers CD34, CD19, and sur....

The Medscape Reference 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.[2, 3]

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.[4, 5, 6, 7]

BTK is necessary for the proliferation and the differentiation of B lymphocytes.[8, 9, 10] 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.

Medicolegal concerns may include the following:

Etiology

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.

Epidemiology

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.

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.[11, 12] 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.

Prognosis

Patients with XLA have survived into their late 40s. The prognosis is good as long as patients are diagnosed and treated early with regular intravenous gamma globulin therapy before the sequelae of recurrent infections appear.[13]

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.

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.

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.[14, 15]  A combination of flow cytometry and Bruton tyrosine kinase gene analysis may be beneficial for carrier screening.[16]

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.

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.[3] 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).[17] Individuals who are affected may have an increased incidence of autoimmune diseases leading to thrombocytopenia, neutropenia, hemolytic anemia, and rheumatoid arthritis.[18] Persistent enteroviral infections may rarely lead to fatal encephalitis or a dermatomyositis-meningoencephalitis syndrome.[19] 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, infection enteritis, and inflammatory bowel disease.[20] 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. They may develop extensive molluscum contagiosum.[21]

Ureaplasma and Mycoplasma infections may be more common than in the general population, as are bladder and joint infections.

Its diagnosis may be delayed due to insufficient awareness in a population with frequent infections in immunocompetent children.[22] Delayed diagnosis and atypical manifestations may also be related to mutation type and BTK expression.[23]

Physical Examination

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.

Pyoderma gangrenosum – like ulcers and cellulitis of the lower extremities may be seen with X-linked (Bruton) agammaglobulinemia.[24] They may occur with recurrent fever and be caused by Helicobacter bilis, an organism difficult recover in blood and wound cultures that can be identified using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry.

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. XLA patients have an increased risk of lymphoma.[25]

Laboratory 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 X-linked agammaglobulinemia (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).

Molecular genetic testing may establish an early confirmed diagnosis of congenital agammaglobulinemia and facilitate carrier detection and prenatal diagnosis.[30] . From a developing country, blood can be blotted onto the filter paper of Guthrie cards and shipped to a laboratory in the United States for sequencing.[31] In fact, the use of molecular genetic tests for early diagnosis should be stressed.[32]

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 X-linked agammaglobulinemia (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.

Medical Care

No curative therapy exists for X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia. Treatment for XLA is IVIG.[33] 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.[34]

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.

Infliximab has been used with X-linked agammaglobulinemia in a patient with associated granulomatous small bowel enteropathy.[35]

Nutritional supplementation with multivitamins is recommended.

The feasibility of using gene-corrected hematopoietic stem cells to complement the immune defects in mouse models has been studied. It may be propitious to initiate stem cell–based therapy for XLA using gene-corrected autologous hematopoietic stem cells.[36]  More recent efforts suggest restoring Bruton tyrosine kinase may be practical as a future therapeutic option.[37]  Human hematopoietic stem cell gene editing may be utilized to rescue B-cell development.[38]

Further inpatient care

Patients with X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, are hospitalized for severe infections or acute decompensation.

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.

Surgical Care

Surgical intervention for X-linked agammaglobulinemia (XLA) 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.

Hematopoietic stem cell transplantation may produce a complete cure. Treosulfan-based reduced toxicity hematopoietic stem cell transplantation may be a good option.[39]

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

Consultations

Consult specialists in genetics, dermatology, gastroenterology, pulmonology, infectious diseases, and hematology. XLA may be due to a mutation de novo, but one should distinguish that low-level maternal gonosomal mosaicism to avoid misinterpretation of risk of recurrence, important for genetic counseling.[40]

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.

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.

A BTK gene mutation screening study may be performed in families with the BTK gene defect to detect new cases. In one study from Taiwan, 52 members of 4 unrelated families with the BTK gene defect for BTK gene mutation detected 6 symptomatic living affected individuals and 11 asymptomatic female carriers.[41]

Long-Term Monitoring

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.

Medication Summary

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

Immune globulin intravenous (Gamimune, Gammar-P, Sandoglobulin, Gammagard)

Clinical Context:  Immune globulin intravenous neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; and may increase CSF IgG (10%).

Adjust the dose and interval according to individual needs.

Symptomatic adverse effects may be alleviated by premedicating with acetaminophen, diphenhydramine, or methylprednisolone (Solu-Medrol).

Class Summary

Immunoglobulins were used as a modality originally with X-linked agammaglobulinemia in 1952 by Colonel Ogden Bruton; immunoglobulin replacement therapy remains important today.[42] 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.

Amoxicillin (Amoxil, Trimox, Biomox)

Clinical Context:  Amoxicillin interferes with the synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Ceftriaxone (Rocephin)

Clinical Context:  Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone arrests bacterial growth by binding to one or more penicillin-binding proteins.

Vancomycin (Vancocin, Lyphocin, Vancoled)

Clinical Context:  Vancomycin is a potent antibiotic directed against gram-positive organisms and active against Enterococcus species. It is useful in the treatment of septicemia and skin structure infections. Ii 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, the current recommendation is to assay trough levels after the third dose, drawn 0.5 hours prior to next dosing. Use creatinine clearance to adjust the dose in patients with renal impairment.

Vancomycin is used in conjunction with gentamicin for prophylaxis in patients allergic to penicillin undergoing GI or GU tract procedures.

Clarithromycin (Biaxin)

Clinical Context:  Clarithromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Class Summary

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.

Albuterol (Proventil, Ventolin)

Clinical Context:  Albuterol is a beta-agonist for bronchospasm refractory to epinephrine. It relaxes bronchial smooth muscle by its action on beta2-receptors, with little effect on cardiac muscle contractility.

Salmeterol (Serevent)

Clinical Context:  By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, salmeterol can relieve bronchospasms. The effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at higher or more frequent doses than recommended.

Class Summary

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.

Beclomethasone, inhaled (Qvar)

Clinical Context:  Beclomethasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn, decreasing airway hyperresponsiveness.

Fluticasone inhaled (Flovent)

Clinical Context:  Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn, decreasing airway hyperresponsiveness.

Class Summary

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

What is X-linked agammaglobulinemia (XLA)?What is the pathophysiology of X-linked agammaglobulinemia (XLA)?How is X-linked agammaglobulinemia (XLA) diagnosed?What causes X-linked agammaglobulinemia (XLA)?What is the prevalence of X-linked agammaglobulinemia (XLA)?What are the racial predilections of X-linked agammaglobulinemia (XLA)?What are the sexual predilections of X-linked agammaglobulinemia (XLA)?At what age does X-linked agammaglobulinemia (XLA) typically present?What is the prognosis of X-linked agammaglobulinemia (XLA)?What is included in patient education about X-linked agammaglobulinemia (XLA)?Which clinical history findings are characteristic of X-linked agammaglobulinemia (XLA)?Which physical findings are characteristic of X-linked agammaglobulinemia (XLA)?What are the possible complications of X-linked agammaglobulinemia (XLA)?Which conditions are included in the differential diagnoses of X-linked agammaglobulinemia (XLA)?What are the differential diagnoses for X-Linked (Bruton) Agammaglobulinemia?What is the role of lab tests in the workup of X-linked agammaglobulinemia (XLA)?What is the role of imaging studies in the workup of X-linked agammaglobulinemia (XLA)?What is the role of pulmonary function tests in the workup of X-linked agammaglobulinemia (XLA)?Which invasive procedures may be used in the workup of X-linked agammaglobulinemia (XLA)?Which histologic findings are characteristic of X-linked agammaglobulinemia (XLA)?How is X-linked agammaglobulinemia (XLA) treated?When is inpatient care indicated for the treatment of X-linked agammaglobulinemia (XLA)?What is the role of surgery in the treatment of X-linked agammaglobulinemia (XLA)?Which specialist consultations are beneficial to patients with X-linked agammaglobulinemia (XLA)?Which dietary modifications are used in the treatment of X-linked agammaglobulinemia (XLA)?Which activity modifications are used in the treatment of X-linked agammaglobulinemia (XLA)?How is X-linked agammaglobulinemia (XLA) diagnosed prenatally?What is included in the long-term monitoring of X-linked agammaglobulinemia (XLA)?What is the role of medications in the treatment of X-linked agammaglobulinemia (XLA)?Which medications in the drug class Corticosteroids are used in the treatment of X-Linked (Bruton) Agammaglobulinemia?Which medications in the drug class Bronchodilators are used in the treatment of X-Linked (Bruton) Agammaglobulinemia?Which medications in the drug class Antibiotics are used in the treatment of X-Linked (Bruton) Agammaglobulinemia?Which medications in the drug class Immunoglobulins are used in the treatment of X-Linked (Bruton) Agammaglobulinemia?

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Franklin Desposito, MD, Professor of Pediatrics and Clinical Director, Center for Human and Molecular Genetics, Rutgers New Jersey Medical School; Consulting Staff, Department of Pediatrics, UMDNJ-University Hospital

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD, Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Julie R Kenner, MD, PhD, Private Practice, SkinHappy MD

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Isabel N. Granja Jander, MD, to the development and writing of this article.

References

  1. Agrebi N, Gentilcore G, Grivel JC, et al. X-Linked Agammaglobulinemia Case with TH Domain Missense Mutation in Bruton Tyrosine Kinase. J Clin Immunol. 2021 May. 41 (4):825-8. [View Abstract]
  2. Conley ME, Broides A, Hernandez-Trujillo V, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev. 2005 Feb. 203:216-34. [View Abstract]
  3. Riccardi N, Rotulo GA, Favilli F, Loy A, Moratto D, Giliani S, et al. Pseudomonas aeruginosa severe skin infection in a toddler with X-linked agammaglobulinemia due to a novel BTK mutation. Infez Med. 2019 Mar 1. 27 (1):73-76. [View Abstract]
  4. Vihinen M, Kwan SP, Lester T, et al. Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia. Hum Mutat. 1999. 13(4):280-5. [View Abstract]
  5. Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA). Front Biosci. 2000 Dec 1. 5:D917-28. [View Abstract]
  6. Wang XC, Wang Y, Kanegane H, Toshio M, Yu YH. [Gene diagnosis of X-linked agammaglobulinemia]. Zhonghua Er Ke Za Zhi. 2005 Jun. 43(6):449-52. [View Abstract]
  7. Wang Y, Kanegane H, Sanal O, et al. Bruton tyrosine kinase gene mutations in Turkish patients with presumed X-linked agammaglobulinemia. Hum Mutat. 2001 Oct. 18(4):356. [View Abstract]
  8. Khan WN. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. Immunol Res. 2001. 23(2-3):147-56. [View Abstract]
  9. 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. 2004 Oct 4. 200(7):927-34. [View Abstract]
  10. Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and function: a genetic perspective. Immunol Rev. 2000 Jun. 175:120-7. [View Abstract]
  11. Poizeau F, Droitcourt C, Saillard C, et al. [Shifting cellulitis in a patient with X-linked hypogammaglobulinemia]. Ann Dermatol Venereol. 2016 Jun-Jul. 143 (6-7):453-6. [View Abstract]
  12. Giorgetti OB, Paolini MV, Oleastro MM, Fernández Romero DS. [X-linked agammaglobulinemia in adults. Clinical evolution]. Medicina (B Aires). 2016. 76 (2):65-70. [View Abstract]
  13. Chun JK, Lee TJ, Song JW, Linton JA, Kim DS. Analysis of clinical presentations of Bruton disease: a review of 20 years of accumulated data from pediatric patients at Severance Hospital. Yonsei Med J. 2008 Feb 29. 49(1):28-36. [View Abstract]
  14. 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. 2001 Jul. 114(1):141-9. [View Abstract]
  15. Speletas M, Kanariou M, Kanakoudi-Tsakalidou F, 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. 2001 Sep. 54(3):321-7. [View Abstract]
  16. Chear CT, Ripen AM, Mohamed SA, Dhaliwal JS. A novel BTK gene mutation creates a de-novo splice site in an X-linked agammaglobulinemia patient. Gene. 2015 Apr 15. 560 (2):245-8. [View Abstract]
  17. Ariganello P, Angelino G, Scarselli A, Salfa I, Della Corte M, De Matteis A, et al. Relapsing Campylobacter jejuni Systemic Infections in a Child with X-Linked Agammaglobulinemia. Case Rep Pediatr. 2013. 2013:735108. [View Abstract]
  18. Fu JL, Shyur SD, Lin HY, Lai YC. X-linked agammaglobulinemia presenting as juvenile chronic arthritis: report of one case. Acta Paediatr Taiwan. 1999 Jul-Aug. 40(4):280-3. [View Abstract]
  19. 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. 2000 Nov. 19(11):1106-8. [View Abstract]
  20. Barmettler S, Otani IM, Minhas J, Abraham RS, Chang Y, Dorsey MJ, et al. Gastrointestinal Manifestations in X-linked Agammaglobulinemia. J Clin Immunol. 2017 Apr. 37 (3):287-294. [View Abstract]
  21. Banday AZ, Jindal AK, Arora K, Rawat A. Extensive Molluscum Contagiosum in X-Linked Agammaglobulinemia. J Allergy Clin Immunol Pract. 2021 Feb. 9 (2):985. [View Abstract]
  22. Vu QV, Wada T, Le HT, Le HT, Van Nguyen AT, Osamu O, et al. Clinical and mutational features of Vietnamese children with X-linked agammaglobulinemia. BMC Pediatr. 2014 May 28. 14:129. [View Abstract]
  23. Carrillo-Tapia E, García-García E, Herrera-González NE, et al. Delayed diagnosis in X-linked agammaglobulinemia and its relationship to the occurrence of mutations in BTK non-kinase domains. Expert Rev Clin Immunol. 2018 Jan. 14 (1):83-93. [View Abstract]
  24. Murray PR, Jain A, Uzel G, Ranken R, Ivy C, Blyn LB, et al. Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: identification of Helicobacter bilis by mass spectrometry analysis. Arch Dermatol. 2010 May. 146(5):523-6. [View Abstract]
  25. Park JY, Kim YS, Shin DH, Choi JS, Kim KH, Bae YK. Primary cutaneous peripheral T-cell lymphoma in a patient with X-linked agammaglobulinaemia. Br J Dermatol. 2011 Mar. 164(3):677-9. [View Abstract]
  26. Narula G, Currimbhoy Z. Transient myelodysplastic syndrome in X-linked agammaglobulinemia with a novel Btk mutation. Pediatr Blood Cancer. 2008 Dec. 51(6):826-8. [View Abstract]
  27. Brosens LA, Tytgat KM, Morsink FH, et al. Multiple colorectal neoplasms in X-linked agammaglobulinemia. Clin Gastroenterol Hepatol. 2008 Jan. 6(1):115-9. [View Abstract]
  28. Behniafard N, Aghamohammadi A, Abolhassani H, Pourjabbar S, Sabouni F, Rezaei N. Autoimmunity in X-linked agammaglobulinemia: Kawasaki disease and review of the literature. Expert Rev Clin Immunol. 2012 Feb. 8(2):155-9. [View Abstract]
  29. Sharma D, Guleria S, Suri D, Rawat A, Garg R, Singh S. A child with X-linked agammaglobulinemia and Kawasaki disease: an unusual association. Rheumatol Int. 2017 Aug. 37 (8):1401-3. [View Abstract]
  30. Qin X, Jiang LP, Tang XM, Wang M, Liu EM, Zhao XD. Clinical features and mutation analysis of X-linked agammaglobulinemia in 20 Chinese patients. World J Pediatr. 2013 Aug. 9 (3):273-7. [View Abstract]
  31. Segundo GRS, Nguyen ATV, Thuc HT, Nguyen LNQ, Kobayashi RH, Le HT, et al. Dried Blood Spots, an Affordable Tool to Collect, Ship, and Sequence gDNA from Patients with an X-Linked Agammaglobulinemia Phenotype Residing in a Developing Country. Front Immunol. 2018. 9:289. [View Abstract]
  32. Doğruel D, Serbes M, Şaşihüseyinoğlu AŞ, Yılmaz M, Altıntaş DU, Bişgin A. Clinical and genetic profiles of patients with X-linked agammaglobulinemia from southeast Turkey: Novel mutations in BTK gene. Allergol Immunopathol (Madr). 2019 Jan - Feb. 47 (1):24-31. [View Abstract]
  33. 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. 2000 Sep-Oct. 22(5):485-7. [View Abstract]
  34. Eijkhout HW, van Der Meer JW, Kallenberg CG, 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. 2001 Aug 7. 135(3):165-74. [View Abstract]
  35. Davey PT, Tan CJ, Gardiner K. The use of infliximab in X-linked agammaglobulinaemia associated enteropathy. Ann R Coll Surg Engl. 2014 Jul. 96(5):e5-6. [View Abstract]
  36. Hendriks RW, Bredius RG, Pike-Overzet K, Staal FJ. Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man. Expert Opin Ther Targets. 2011 Aug. 15(8):1003-21. [View Abstract]
  37. Bestas B, Turunen JJ, Blomberg KE, Wang Q, Månsson R, El Andaloussi S, et al. Splice-correction strategies for treatment of X-linked agammaglobulinemia. Curr Allergy Asthma Rep. 2015 Mar. 15 (3):510. [View Abstract]
  38. Bahal S, Zinicola M, Moula SE, et al. Hematopoietic stem cell gene editing rescues B-cell development in X-linked agammaglobulinemia. J Allergy Clin Immunol. 2024 Mar 11. [View Abstract]
  39. Vellaichamy Swaminathan V, Uppuluri R, Patel S, Melarcode Ramanan K, Ravichandran N, Jayakumar I, et al. Treosulfan-based reduced toxicity hematopoietic stem cell transplantation in X-linked agammaglobulinemia: A cost-effective alternative to long-term immunoglobulin replacement in developing countries. Pediatr Transplant. 2020 Feb. 24 (1):e13625. [View Abstract]
  40. Rivière JG, Franco-Jarava C, Martínez-Gallo M, Aguiló-Cucurull A, Blasco-Pérez L, Paramonov I, et al. Uncovering Low-Level Maternal Gonosomal Mosaicism in X-Linked Agammaglobulinemia: Implications for Genetic Counseling. Front Immunol. 2020. 11:46. [View Abstract]
  41. Lee KH, Shyur SD, Chu SH, Huang LH, Kao YH, Lei WT, et al. Clinical manifestations and BTK gene defect in 4 unrelated Taiwanese families with Bruton's disease. Asian Pac J Allergy Immunol. 2011 Sep. 29(3):260-5. [View Abstract]
  42. Sil A, Basu S, Joshi V, et al. Immunoglobulin replacement therapies in inborn errors of immunity: a review. Front Pediatr. 2024. 12:1368755. [View Abstract]

Early stages of B-cell differentiation can be identified by the status of the immunoglobulin genes and by the cell surface markers CD34, CD19, and surface immunoglobulin (sIg). From: Conley ME. Genes required for B cell development. J Clin Invest. 2003;112: 1636-8. Reproduced with permission of American Society for Clinical Investigation via Copyright Clearance Center.

Early stages of B-cell differentiation can be identified by the status of the immunoglobulin genes and by the cell surface markers CD34, CD19, and surface immunoglobulin (sIg). From: Conley ME. Genes required for B cell development. J Clin Invest. 2003;112: 1636-8. Reproduced with permission of American Society for Clinical Investigation via Copyright Clearance Center.