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].

respiratoric
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  • Face, Head & Neck
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  • Entire body system
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  • 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].

    Laboratory

    Serum
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  • Microbiology
    Staphylococcus Aureus
    • Patients display infection susceptibility to pyogenic bacteria such as Staphylococcus aureus , Streptococcus pneumoniae , and Haemophilus influenzae .[pathwaymedicine.org]
    • aureus , Salmonella spp and Giardia spp and enterovirus.[orpha.net]
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  • Treatment

    Prognosis

    Complications

    Renal Amyloidosis
    • Renal amyloidosis in a patient with X-linked agammaglobulinemia (Bruton's disease) and bronchiectasis. J Clin Immunol . Jan 2014. 34:119-22. [Medline] . Howard V, Myers LA, Williams DA, et al.[emedicine.medscape.com]
    Alopecia Totalis
    • Rare patients are reported to have vitiligo, erythematous rash, or alopecia totalis. Infections tend to persist throughout adulthood. Affected patients are reported to have a higher susceptibility to severe and chronic enteroviral infections.[orpha.net]

    Etiology

    Epidemiology

    Sex distribution
    Age distribution

    Pathophysiology

    Prevention

    Summary

    Patient Information

    Other symptoms

    No Opportunistic Infections
    • 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[symptoma.com]
    • They note that major indications of these disorders include multiple infections despite appropriate therapy, failure to thrive, opportunistic infections, and a positive family history. Stewart et al. review the clinical spectrum of XLA.[medbullets.com]
    Lung Transplantation
    • Bronchiolitis obliterans syndrome, hypogammaglobulinemia, and infectious complications of lung transplantation. J Heart Lung Transplant . Jan 2013. 32:36-43. [Medline] .[emedicine.medscape.com]
    • Completed NCT00278954 Phase 3 15 EZN-2279 in Patients With ADA-SCID Recruiting NCT01420627 Phase 3 16 Intravenous Immunoglobulin (IVIG) in Lung Transplantation Unknown status NCT00115778 Phase 2 Intravenous immunoglobulin 17 Safety, Pharmacokinetic and[malacards.org]
    Sensory Deficits
    • At age 15 years, the boy developed megaloblastic anemia, sensory deficit in both legs and ataxia. Diagnosis of combined iron deficiency and vitamin B 12 deficiency was made.[journals.lww.com]
    Non-Progressive
    • Non-progressive viral myelitis in X-linked agammaglobulinemia. Brain Dev . 2002 Mar. 24(2):109-11. [Medline] . Wildenbeest JG, van den Broek PJ, Benschop KS, et al.[emedicine.medscape.com]
    Cerebellar Hypoplasia
    • A syndrome involving intrauterine growth retardation, microcephaly, cerebellar hypoplasia, B lymphocyte deficiency, and progressive pancytopenia. Pediatrics . 2000 Mar. 105(3):E39. [Medline] . Roifman CM.[emedicine.medscape.com]
    Normal Cell-Mediated Immunity
    • In our patient, the diagnosis of agammaglobulinemia was confirmed by her extremely low concentration of all the immunoglobulin isotypes, profound decrease in circulating B-lymphocytes, normal lymphocyte count and normal cell-mediated immunity, complement[scielo.br]
    Melphalan
    • Melphalan (JP15/USP/INN) MELPHALAN (SEE ALSO TRANSGENIC MODEL EVALUATION (MELPHALAN)) Melphalan [USAN:INN:BAN:JAN] Melphalanum Melphalanum [INN-Latin] Mephalan MLS001333666 MLS002153368 MolPort-003-665-535 NCGC00090757-01 NCGC00090757-02 NCGC00090757[malacards.org]

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    References

    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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