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Agammaglobulinemia

Agammaglobulinemia is a form of primary immunodeficiency demarcated by defects in B-cell function due to gene mutations encoding the Bruton tyrosine kinase protein on chromosome X, which is why the term X-linked agammaglobulinemia is used in the literature. Recurrent bacterial infections of the skin, lungs and the gastrointestinal tract appearing in infancy are the main clinical presentation. The diagnosis is made based on clinical and laboratory criteria, as well as genetic studies.


Presentation

Signs and symptoms of agammaglobulinemia (often referred as X-linked agammaglobulinemia, or XLA) start to appear several months after birth (between 7-9 months of age in most cases) when maternal immunoglobulins in the child slowly begin to disappear, and are completely absent at the end of the child's first year of life [1] [2]. Having in mind the complete or near-complete dysfunction of B-cells due to mutations in the Bruton tyrosine kinase (BTK) protein, situated on the X chromosome (resulting in almost exclusive appearance of the disease in males), infants are predisposed to numerous infections of bacterial, viral and fungal origin, and their recurrent appearance is usually the first and most important clinical presentation [3] [4]. In particular, patients are most susceptible to infections caused by encapsulated bacteria (such as streptococcus pneumoniae, haemophilus influenzae, and pseudomonas aeruginosa), mycoplasma spp., enteroviruses and giardia lamblia [4] [5]. Recurrent infections of the respiratory system (pneumonia and less commonly sinusitis), skin, the gastrointestinal tract (caused by rotavirus, salmonella spp., and campylobacter spp., in addition to giardiasis) are typical for agammaglobulinemia patients, and recurrent otitis media is described in the vast majority of cases [1] [4] [6]. Central nervous system (CNS) infections, both meningitis, and encephalitis, as well as sepsis and infections of the musculoskeletal system (osteomyelitis and arthritis), can develop in the absence of a timely diagnosis [1] [4] [6]. Hand-foot-and-mouth disease, hepatitis, opportunistic infections (pneumocystis jiroveci pneumonia - PCP) and polio vaccine-related poliomyelitis (as a result of depleted B-cells) are very rare manifestations of agammaglobulinemia but have been reported by certain authors [1] [4] [7].

Pathologist
  • This description may help the pathologist in considering a differential diagnosis when examining a diagnostic lymph node biopsy in these patients.[ncbi.nlm.nih.gov]
  • PMID: 21039741 Assay Assay and technical information Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion[invitae.com]
Aspiration
  • Bone marrow aspirates showed less than 0.01% CD19 B cells with normal percentages of TdT VpreB CD19- B cell precursors.[emedicine.com]
Dystonia
  • A progressive, fatal dystonia-Parkinsonism syndrome in a patient with primary immunodeficiency receiving chronic IBIG therapy. Mov Disord. 2007. 22:1664-6. [Medline]. Cunningham-Rundles C.[emedicine.com]
  • A progressive, fatal dystonia-Parkinsonism syndrome in a patient with primary immunodeficiency receiving chronic IBIG therapy. Mov Disord . 2007. 22:1664-6. [Medline] . Cunningham-Rundles C.[emedicine.medscape.com]

Workup

The diagnosis of agammaglobulinemia can be made only if physicians recognize the recurrent nature of infections in infancy and early childhood and order a thorough laboratory investigation. Despite evident clinical criteria for some form of immunodeficiency, however, up to 20% of children are not diagnosed by school age, indicating that clinical suspicion is probably the most important factor in detecting agammaglobulinemia [1] [3] [6]. A detailed patient history focused on the interview with the parents (as children are often too young to provide relevant information) can provide vital clues for the physician. A detailed family history is equally important and may be quite useful in determining whether close family members have or had the diagnosis or experience of similar symptoms, as a significant number of patients have a confirmed family member suffering from agammaglobulinemia [6]. Initial laboratory testing reveals neutropenia in about 15% of cases, whereas reductions in serum immunoglobulins (IgG, IgM and IgA) are readily encountered [1] [5] [6] [8]. A key diagnostic feature of agammaglobulinemia is a markedly lower number of CD19+ B cells (< 2%), while absent isohemagglutinins and/or poor vaccine responses are also important features that make the diagnosis of this primary immunodeficiency highly likely [1] [8]. Confirmation of agammaglobulinemia, however, is achieved by detecting BTK mutations through genetic studies in both the patient and in one of his maternal cousins [1].

Mycoplasma Hominis
  • In-vitro activities of tetracyclines, macrolides, fluoroquinolones and clindamycin against Mycoplasma hominis and Ureaplasma ssp. isolated in Germany over 20 years. Clin Microbiol Infect, 2010; 16(11):1649-55. [ PubMed ] [ CrossRef ].[journal-imab-bg.org]
  • Hypogammaglobulinemic patient with polyarthritis mimicking rheumatoid arthritis finally diagnosed as septic arthritis caused by Mycoplasma hominis. Intern Med. 2012. 51:425-9. [Medline]. Sukumaran S, Marzan K, Shaham B, Church JA.[emedicine.com]
  • Hypogammaglobulinemic patient with polyarthritis mimicking rheumatoid arthritis finally diagnosed as septic arthritis caused by Mycoplasma hominis. Intern Med . 2012. 51:425-9. [Medline] . Sukumaran S, Marzan K, Shaham B, Church JA.[emedicine.medscape.com]
Giardia Lamblia

Treatment

  • Prolonged suboptimal treatment may cause bacterial resistance to β-lactam antibiotics in H. cinaedi. It is possible that this resistance may have contributed to the treatment failure.[ncbi.nlm.nih.gov]
  • Nevertheless, some frequent affections persist despite treatment, and lead to handicapping and further to morbid clinical complications for XLA individuals.[eurekaselect.com]
  • While efficient, the current life-maintaining therapy with immunoglobulins and antibiotics is non-curative, prompting research into alternative treatment strategies that aim at rescuing the expression of the affected protein, thus giving rise to functional[ncbi.nlm.nih.gov]
  • Management and treatment There is no curative treatment but good disease control can be achieved through consistent gammaglobulin therapy. This can be given intravenously (400-600 mg/kg every 3 to 4 weeks) or subcutaneously (100 mg/kg every week).[orpha.net]
  • And treatment for your frequently active infections will probably require an antibiotic . With treatment you can expect to live a long, healthy life. Without treatment, some bacterial infections that might not otherwise be fatal, may be for you.[healthblurbs.com]

Prognosis

  • Prognosis The prognosis depends on the age at diagnosis, compliance with therapy and the development of complications. Most patients on treatment can lead a normal life.[orpha.net]
  • , Prevention, and Complications Prognosis normal prognosis with regular IVIG therapy and early detection Prevention screening in newborns regular IVIG to prevent infections Complications small risk of malignancy Please rate topic.[step1.medbullets.com]
  • Diagnosis - X-Linked Agammaglobulinemia Prognosis - X-Linked Agammaglobulinemia Not supplied. Treatment - X-Linked Agammaglobulinemia Resources - X-Linked Agammaglobulinemia Not supplied.[checkorphan.org]

Etiology

  • Etiology The disorder is due to mutations in various genes involved in humoral immunity, including: IGHM (14q32.33), BLNK (10q23.2-q23.33), CD79A (19q13.2), CD79B (17q23), IGLL1 (22q11.23), PIK3R1 (5q13.1) and TCF3 (19p13.3) Common causative microorganisms[orpha.net]
  • Etiology XLA is caused by mutations in the BTK gene (Xq21.33-q22) involved in B lymphocyte differentiation and maturation.[orpha.net]
  • Epidemiology and etiology of childhood pneumonia . Bulletin of the World Health Organization 2008; 86: 408-416 9 Stein RT, Marostica PJ. Community-acquired pneumonia: a review and recent advances .[thieme-connect.com]
  • (Etiology) The causative factors of Bruton’s Agammaglobulinemia include mutations in the BTK gene, located on the X chromosome.[dovemed.com]

Epidemiology

  • Vach 3 Clinical Epidemiology, Institute of Medical Biometry and Medical Informatics, University Medical Centre, University of Freiburg, Germany , M.[thieme-connect.com]
  • Summary Epidemiology Fewer than 100 cases of autosomal inherited agammaglobulinemia have been reported to date.[orpha.net]
  • […] autosomal dominant variants may be difficult to differentiate from X-linked disease (eg, LRRC8A variants) Differential Diagnosis X-linked hyper IgM syndrome X-linked severe combined immunodeficienc y X-linked lymphoproliferative disease HIV Background Epidemiology[arupconsult.com]
  • […] cytometry – if protein expression is absent or reduced, suggests X-linked agammaglobulinemia (XLA) in males Differential Diagnosis X-linked hyper IgM syndrome X-linked severe combined immunodeficienc y X-linked lymphoproliferative disease HIV Background Epidemiology[arupconsult.com]
  • Summary Epidemiology Estimated prevalence is 1/350,000 to 1/700,000. Annual incidence is not known. The disorder has been reported in various ethnic groups worldwide. Only males are affected and females are asymptomatic carriers.[orpha.net]
Sex distribution
Age distribution

Pathophysiology

  • […] immunodeficienc y X-linked lymphoproliferative disease HIV Background Epidemiology Incidence – estimated 1/250,000-700,000 male births Age 50% diagnosed by 2 years 80% diagnosed by 5 years Sex – 99% male Ethnicity – most commonly diagnosed in Caucasians Pathophysiology[arupconsult.com]
  • In addition to the genetic defects described above, other pathophysiology mechanisms may result in hypogammaglobulinemia or agammaglobulinemia, such as viral infections, malignancy, or drug effects. These are described in more detail in Causes.[emedicine.com]
  • Pathophysiology In the absence of BTK, B lymphocytes do not differentiate or mature. Without mature B lymphocytes, antibody-producing plasma cells are also absent.[emedicine.medscape.com]
  • Bruton Pathophysiology Thomas A.E. Plattes-Mills. Middleton's Allergy 8th Edition. 1144-74. Conley ME, et al. Immunological Reviews 2005. Vol. 203: 216–234. Vetrie D, et al. Nature1993;361:226–233. Tsukada S, et al. Cell 1993;72:279–290. 8.[slideshare.net]

Prevention

  • Frequently called Bruton's Agammaglobulinemia, XLA is caused by a genetic mistake in a gene called Bruton's Tyrosine Kinase (BTK), which prevents B cells from developing normally.[aaaai.org]
  • These mutations prevent the development and regulation of B lymphocytes Pre-B-lymphocytes are unable to mature into B lymphocytes.[dovemed.com]
  • It should be noted here that children with Agammaglobulinemia should not get live vaccinations as the child may end up having the disease for which vaccinations were given instead of preventing it.[epainassist.com]

References

Article

  1. Machado P, Santos A, Faria E, Silva J, Malcata A, Chieira C. Arthritis and X-linked agammaglobulinemia. Acta Reumatol Port. 2008;33(4):464-467.
  2. Ozturk C, Sutcuoglu S, Atabay B, Berdeli A. X-Linked Agammaglobulinemia Presenting with Secondary Hemophagocytic Syndrome: A Case Report. Case Reports in Medicine. 2013;2013:742795.
  3. Sigmon JR, Kasasbeh E, Krishnaswamy G. X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature. Clinical and molecular allergy : CMA. 2008;6:5.
  4. Chen X-F, Wang W-F, Zhang Y-D, Zhao W, Wu J, Chen T-X. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000–2015). Medicine (Baltimore). 2016;95(32):e4544.
  5. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, et al. Autoimmunity and Inflammation in X-linked Agammaglobulinemia. J Clin Immunol. 2014;34(6):627-632.
  6. Winkelstein JA, Marino MC, Lederman HM, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006;85(4):193-202.
  7. Jongco AM, Gough JD, Sarnataro K, et al. X-linked agammaglobulinemia presenting as polymicrobial pneumonia, including Pneumocystis jirovecii. Ann Allergy Asthma Immunol. 2014;112(1):10.1016/j.anai.2013.10.008.
  8. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.

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Last updated: 2019-07-11 21:24