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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].

    Skin
    Pruritus
    • In either case, mild allergic reactions (generalized pruritus, urticaria) are common, and are usually manageable with oral diphenhydramine.[en.wikipedia.org]
    Urticaria
    • In either case, mild allergic reactions (generalized pruritus, urticaria) are common, and are usually manageable with oral diphenhydramine.[en.wikipedia.org]
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  • respiratoric
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  • Entire body system
    Falling
    • The percentage of cells within the lymphoid gate that fall into each of the sectors is shown.[jem.rupress.org]
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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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  • Treatment

    Prognosis

    Complications

    Osteopetrosis
    • Mice lacking Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. 62 At this time, there are no clinical trials using BTK inhibition in autoimmune diseases, but it is expected that these will commence within the near future.[jco.ascopubs.org]
    Mental Retardation
    • X-linked mental retardation with isolated growth hormone deficiency is mapped to Xq22-Xq27.2 in one family.[emedicine.medscape.com]
    Urticaria
    • In either case, mild allergic reactions (generalized pruritus, urticaria) are common, and are usually manageable with oral diphenhydramine.[en.wikipedia.org]
    Upper Respiratory Infection
    • Snapshot A 6-year-old boy presents to the hospital with a severe upper respiratory infection requiring hospitalization.[medbullets.com]

    Etiology

    Epidemiology

    Sex distribution
    Age distribution

    Pathophysiology

    Prevention

    Summary

    Patient Information

    Other symptoms

    Hypogammaglobulinemia
    • Saul Greenberg: "Hypogammaglobulinemia ".[en.wikipedia.org]
    • ICD-10-CM Diagnosis Code D80.1 Nonfamilial hypogammaglobulinemia 2016 2017 2018 Billable/Specific Code Applicable To Agammaglobulinemia with immunoglobulin-bearing B-lymphocytes Common variable agammaglobulinemia [CVAgamma] Hypogammaglobulinemia NOS[icd10data.com]
    • X linked hypogammaglobulinemia X-linked agammaglobulinemia X-linked hypogammaglobulinemia Applies To Agammaglobulinemia: Bruton's type X-linked ICD-9-CM Volume 2 Index entries containing back-references to 279.04 :[icd9data.com]
    • Any factor that impedes the development of the B cell lineage and/or the function of mature B cells may result in levels of serum immunoglobulins that are reduced (ie, hypogammaglobulinemia) or nearly absent (ie, agammaglobulinemia).[uptodate.com]
    Hypogammaglobulinemia
    • Saul Greenberg: "Hypogammaglobulinemia ".[en.wikipedia.org]
    • ICD-10-CM Diagnosis Code D80.1 Nonfamilial hypogammaglobulinemia 2016 2017 2018 Billable/Specific Code Applicable To Agammaglobulinemia with immunoglobulin-bearing B-lymphocytes Common variable agammaglobulinemia [CVAgamma] Hypogammaglobulinemia NOS[icd10data.com]
    • X linked hypogammaglobulinemia X-linked agammaglobulinemia X-linked hypogammaglobulinemia Applies To Agammaglobulinemia: Bruton's type X-linked ICD-9-CM Volume 2 Index entries containing back-references to 279.04 :[icd9data.com]
    • Any factor that impedes the development of the B cell lineage and/or the function of mature B cells may result in levels of serum immunoglobulins that are reduced (ie, hypogammaglobulinemia) or nearly absent (ie, agammaglobulinemia).[uptodate.com]
    Gamma Globulin
    • Hypogammaglobulinemia is a type of primary immunodeficiency disease in which not enough gamma globulins exist in the blood (thus hypo- gamma globulin -emia).[en.wikipedia.org]
    • Agammaglobulinemia The lack of gamma globulins in the blood.[medical-dictionary.thefreedictionary.com]
    • […] noun Medicine Lack of gamma globulin in the blood plasma, causing immune deficiency.[oxforddictionaries.com]
    • […] of long-term antibiotic therapy to furnish protection, and (f) response to protective injections of gamma globulin.[annals.org]
    • Congenital or acquired absence of, or extremely low levels of, gamma globulins in the blood.[dictionary.reference.com]
    Common Variable Immunodeficiency
    • Hypogammaglobulinemia is a characteristic of common variable immunodeficiency.[en.wikipedia.org]
    • Variable Immunodeficiency (CVID) or X-linked agammaglobulinemia ( XLA), age 1 to 70 years Disease: Version SOC Term Classification Code Term Level 8.1 10010112 Common variable immunodeficiency LLT Population Age: Infants and toddlers, Children, Adolescents[clinicaltrialsregister.eu]
    • variable immunodeficiency" ) Literature review current through: Dec 2017.[uptodate.com]
    • X-linked agammaglobulinemia, common variable immunodeficiency, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, and X-linked lymphoproliferative disorder.[journals.lww.com]
    • variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA).[mayomedicallaboratories.com]
    Growth Hormone Deficiency
    • The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia (ARAG).[webmd.com]
    • Applicable To Autosomal recessive agammaglobulinemia (Swiss type) X-linked agammaglobulinemia [Bruton] (with growth hormone deficiency) The following code(s) above D80.0 contain annotation back-references Annotation Back-References In this context, annotation[icd10data.com]
    • MD: The Johns Hopkins University; Hypogammaglobulinemia and isolated growth hormone deficiency, X-linked.[rarediseases.org]
    • hormone deficiency Pneumonia Bacteremia more related diseases...»[rightdiagnosis.com]
    • X-linked hypogammaglobulinemia and isolated growth hormone deficiency: an update.[emedicine.medscape.com]
    Growth Hormone Deficiency
    • The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia (ARAG).[webmd.com]
    • Applicable To Autosomal recessive agammaglobulinemia (Swiss type) X-linked agammaglobulinemia [Bruton] (with growth hormone deficiency) The following code(s) above D80.0 contain annotation back-references Annotation Back-References In this context, annotation[icd10data.com]
    • MD: The Johns Hopkins University; Hypogammaglobulinemia and isolated growth hormone deficiency, X-linked.[rarediseases.org]
    • hormone deficiency Pneumonia Bacteremia more related diseases...»[rightdiagnosis.com]
    • X-linked hypogammaglobulinemia and isolated growth hormone deficiency: an update.[emedicine.medscape.com]
    X-Linked Hypogammaglobulinemia
    • linked hypogammaglobulinemia X-linked agammaglobulinemia X-linked hypogammaglobulinemia Applies To Agammaglobulinemia: Bruton's type X-linked ICD-9-CM Volume 2 Index entries containing back-references to 279.04 :[icd9data.com]
    • linked hypogammaglobulinemia X-linked agammaglobulinemia ICD-10-CM D80.0 is grouped within Diagnostic Related Group(s) (MS-DRG v 35.0): 814 Reticuloendothelial and immunity disorders with mcc 815 Reticuloendothelial and immunity disorders with cc 816[icd10data.com]
    • X-linked hypogammaglobulinemia and isolated growth hormone deficiency: an update.[emedicine.medscape.com]
    Hypersensitivity
    • The selective Ab defect in XLA contributed to the concept of specialized lymphocyte lineages and the discovery by Cooper et al. ( 5 , 6 ) that the B cell lineage was the source of Igs and that T cells regulated delayed-type hypersensitivity and graft[jimmunol.org]
    • Transient hypogammaglobulinemia after antileptic drug hypersensitivity.[emedicine.medscape.com]
    • Mice with p85α deficiency have insulin hypersensitivity, defective platelet function, and abnormal mast cell development.[jem.rupress.org]
    Congenital Disorders
    • Congenital disorders of lymphocyte function.[nlm.nih.gov]
    • However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood.[en.wikipedia.org]
    Systemic Disease
    • AGMX was one of the first immune system diseases identified.[healthline.com]
    • Although astroviruses are commonly associated with gastroenteritis, they have not been associated with central nervous system disease.[wwwnc.cdc.gov]
    Diphenhydramine
    • In either case, mild allergic reactions (generalized pruritus, urticaria) are common, and are usually manageable with oral diphenhydramine.[en.wikipedia.org]
    Dysgammaglobulinemia
    • "Hypogammaglobulinemia" is distinguished from dysgammaglobulinemia, which is a reduction in some types of gamma globulins, but not others.[en.wikipedia.org]
    No Mental Retardation
    • X-linked mental retardation with isolated growth hormone deficiency is mapped to Xq22-Xq27.2 in one family.[emedicine.medscape.com]
    Humoral Defect
    • In Brazil, of 101 cases of humoral deficiencies, XLA was the least frequent (9), compared with IgA deficiency (60) and transient hypogammaglobulinemia (14). [14] In Asians, specifically in Hong Kong, humoral defects were identified in 50 of 117 patients[emedicine.medscape.com]
    Gastrointestinal Disorder
    • Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency.[emedicine.medscape.com]

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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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