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X-linked agammaglobulinemia(XLA)

MedGen UID:
65123
Concept ID:
C0221026
Disease or Syndrome
Synonyms: Agammaglobulinemia, Bruton tyrosine kinase; Agammaglobulinemia, BTK; AGAMMAGLOBULINEMIA, X-LINKED, TYPE 1; Bruton's agammaglobulinemia; Bruton-type agammaglobulinemia; BTK-deficiency; IMMUNODEFICIENCY 1; XLA
SNOMED CT: X-linked agammaglobulinemia (65880007); Bruton's type agammaglobulinemia (65880007); X linked agammaglobulinemia (65880007); Bruton's agammaglobulinemia (65880007); XLA - X-linked agammaglobulinemia (65880007); Bruton's hypogammaglobulinemia (65880007)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): BTK (Xq22.1)
 
Monarch Initiative: MONDO:0010421
OMIM®: 300755
Orphanet: ORPHA47

Disease characteristics

Excerpted from the GeneReview: X-Linked Agammaglobulinemia
X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum immunoglobulin G to be achieved, and more liberal use of antibiotics. [from GeneReviews]
Authors:
CI Edvard Smith  |  Anna Berglöf   view full author information

Additional descriptions

From OMIM
X-linked agammaglobulinemia is an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. The defect in this disorder resides in BTK, also known as BPK or ATK, a key regulator in B-cell development (Rawlings and Witte, 1994). The X-linked form accounts for approximately 85 to 90% of cases of the disorder. Also see 300310. The remaining 15% of cases constitute a heterogeneous group of autosomal disorders (Lopez Granados et al., 2002; Ferrari et al., 2007). Genetic Heterogeneity of Agammaglobulinemia/Hypogammaglobulinemia A form of X-linked hypogammaglobulinemia (IMD61; 300310) is caused by mutation in the SH3KBP1 gene (300374) on chromosome Xq22. See agammaglobulinemia-1 (AGM1; 601495) for a discussion of genetic heterogeneity of autosomal forms of agammaglobulinemia.  http://www.omim.org/entry/300755
From MedlinePlus Genetics
X-linked agammaglobulinemia (XLA) is a condition that affects the immune system and occurs almost exclusively in males. It is part of a group of disorders called primary immunodeficiencies (or inborn errors of immunity), in which part of the immune system does not function as it should. People with XLA have very few B cells, which are specialized white blood cells that help protect the body against infection. B cells can mature into the cells that produce special proteins called antibodies or immunoglobulins. Antibodies attach to specific foreign particles and germs, marking them for destruction. Individuals with XLA are more susceptible to infections because their body makes very few antibodies.

Children with XLA are usually healthy for the first 1 or 2 months of life because they are protected by antibodies acquired before birth from their mother. After this time, the maternal antibodies are cleared from the body, and the affected child begins to develop recurrent infections. .cf0{font-style:italic;font-family:Segoe UI;font-size:9pt;}Children with XLA generally take longer to recover from infections, and infections often occur again, even in children who are taking antibiotic medications.

The most common bacterial infections that occur in people with XLA are lung infections (pneumonia and bronchitis), ear infections (otitis), pink eye (conjunctivitis), and sinus infections (sinusitis). Infections that cause chronic diarrhea are also common. Recurrent infections can lead to organ damage. .cf0{font-style:italic;font-family:Segoe UI;font-size:9pt;}Treatments that replace antibodies can help prevent infections, improving the quality of life for people with XLA.  https://medlineplus.gov/genetics/condition/x-linked-agammaglobulinemia

Clinical features

From HPO
Recurrent urinary tract infections
MedGen UID:
120466
Concept ID:
C0262655
Disease or Syndrome
Repeated infections of the urinary tract.
Cor pulmonale
MedGen UID:
18765
Concept ID:
C0034072
Disease or Syndrome
Right-sided heart failure resulting from chronic hypertension in the pulmonary arteries and right ventricle.
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Enteroviral hepatitis
MedGen UID:
334558
Concept ID:
C1843995
Disease or Syndrome
Inflammation of the liver due to infection with enterovirus.
Hepatocellular carcinoma
MedGen UID:
389187
Concept ID:
C2239176
Neoplastic Process
Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002).
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Infective arthritis
MedGen UID:
13918
Concept ID:
C0003869
Disease or Syndrome
The inflammation of one or more joints caused by any infectious pathogen within the joint space. Symptoms include pain, stiffness, and decreased range of motion in the affected joint.
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Bronchiolitis obliterans with obstructive pulmonary disease
MedGen UID:
665
Concept ID:
C0006272
Disease or Syndrome
Inflammation and fibrosis of the bronchioles leading to partial or complete obstruction of these airways.
Wheezing
MedGen UID:
21917
Concept ID:
C0043144
Sign or Symptom
A high-pitched whistling sound associated with labored breathing.
Recurrent sinusitis
MedGen UID:
107919
Concept ID:
C0581354
Disease or Syndrome
A recurrent form of sinusitis.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Recurrent lower respiratory tract infections
MedGen UID:
756211
Concept ID:
C3163798
Disease or Syndrome
An increased susceptibility to lower respiratory tract infections as manifested by a history of recurrent lower respiratory tract infections.
Agammaglobulinemia
MedGen UID:
168
Concept ID:
C0001768
Disease or Syndrome
A lasting absence of total IgG and total IgA and total IgM in the blood circulation, whereby at most trace quantities can be measured.
Conjunctivitis
MedGen UID:
1093
Concept ID:
C0009763
Disease or Syndrome
Inflammation of the conjunctiva.
Epididymitis
MedGen UID:
4986
Concept ID:
C0014534
Disease or Syndrome
The presence of inflammation of the epididymis.
Meningitis
MedGen UID:
6298
Concept ID:
C0025289
Disease or Syndrome
Inflammation of the meninges.
Prostatitis
MedGen UID:
10965
Concept ID:
C0033581
Disease or Syndrome
The presence of inflammation of the prostate.
Pyoderma
MedGen UID:
18783
Concept ID:
C0034212
Disease or Syndrome
Any manifestation of a skin disease associated with the production of pus.
Sepsis
MedGen UID:
48626
Concept ID:
C0036690
Disease or Syndrome
Systemic inflammatory response to infection.
Decreased circulating IgA level
MedGen UID:
57934
Concept ID:
C0162538
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
Decreased circulating total IgM
MedGen UID:
116095
Concept ID:
C0239989
Finding
An abnormally decreased level of immunoglobulin M (IgM) in blood.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Infectious encephalitis
MedGen UID:
108917
Concept ID:
C0596773
Disease or Syndrome
A disorder of the brain caused by an infectious agent that presents with fever, headache, and an altered level of consciousness. There may also be focal or multifocal neurologic deficits, and focal or generalized seizure activity.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Decreased circulating IgE
MedGen UID:
1714318
Concept ID:
C0853668
Finding
An abnormally decreased level of immunoglobulin E (IgE) in blood.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
B lymphocytopenia
MedGen UID:
340780
Concept ID:
C1855067
Finding
An abnormal decrease from the normal count of B cells.
T lymphocytopenia
MedGen UID:
419385
Concept ID:
C2931322
Finding
An abnormally low count of T cells.
Enteroviral dermatomyositis syndrome
MedGen UID:
812990
Concept ID:
C3806660
Finding
Lymph node hypoplasia
MedGen UID:
892318
Concept ID:
C4025683
Finding
Underdevelopment of the lymph nodes.
Complete or near-complete absence of specific antibody response to Haemophilus influenzae type b (Hib) vaccine
MedGen UID:
1692657
Concept ID:
C5139466
Finding
The inability to synthesize postvaccination antibodies against a Haemophilus influenzae type b (Hib) antigen, as measured by antibody titer determination following vaccination.
Decreased circulating IgG level
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVX-linked agammaglobulinemia
Follow this link to review classifications for X-linked agammaglobulinemia in Orphanet.

Professional guidelines

PubMed

Weinberger T, Fuleihan R, Cunningham-Rundles C, Maglione PJ
J Clin Immunol 2019 May;39(4):440-447. Epub 2019 May 14 doi: 10.1007/s10875-019-00640-5. PMID: 31089938Free PMC Article
Bestas B, Turunen JJ, Blomberg KE, Wang Q, Månsson R, El Andaloussi S, Berglöf A, Smith CI
Curr Allergy Asthma Rep 2015 Mar;15(3):510. doi: 10.1007/s11882-014-0510-0. PMID: 25638286Free PMC Article
Whang JA, Chang BY
Drug Discov Today 2014 Aug;19(8):1200-4. Epub 2014 Apr 12 doi: 10.1016/j.drudis.2014.03.028. PMID: 24721226

Recent clinical studies

Etiology

Jones TPW, Buckland M, Breuer J, Lowe DM
Rev Med Virol 2019 Jul;29(4):e2049. Epub 2019 Apr 24 doi: 10.1002/rmv.2049. PMID: 31016825
Pal Singh S, Dammeijer F, Hendriks RW
Mol Cancer 2018 Feb 19;17(1):57. doi: 10.1186/s12943-018-0779-z. PMID: 29455639Free PMC Article
Kanegane H, Hoshino A, Okano T, Yasumi T, Wada T, Takada H, Okada S, Yamashita M, Yeh TW, Nishikomori R, Takagi M, Imai K, Ochs HD, Morio T
Allergol Int 2018 Jan;67(1):43-54. Epub 2017 Jul 3 doi: 10.1016/j.alit.2017.06.003. PMID: 28684198
Bearden D, Collett M, Quan PL, Costa-Carvalho BT, Sullivan KE
J Allergy Clin Immunol Pract 2016 Nov-Dec;4(6):1059-1065. Epub 2016 Feb 13 doi: 10.1016/j.jaip.2015.12.015. PMID: 26883540
Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, Ochs HD, Bonilla FA, Paris K, Yel L, Sullivan KE
J Clin Immunol 2014 Aug;34(6):627-32. Epub 2014 Jun 10 doi: 10.1007/s10875-014-0056-x. PMID: 24909997Free PMC Article

Diagnosis

Altman K, Zhou C, Hernandez-Trujillo V, Scalchunes C, Rawlings DJ, de la Morena MT
J Clin Immunol 2022 May;42(4):811-818. Epub 2022 Mar 14 doi: 10.1007/s10875-022-01222-8. PMID: 35284987
Cardenas-Morales M, Hernandez-Trujillo VP
Clin Rev Allergy Immunol 2022 Aug;63(1):22-35. Epub 2021 Jul 9 doi: 10.1007/s12016-021-08870-5. PMID: 34241796Free PMC Article
Kanegane H, Hoshino A, Okano T, Yasumi T, Wada T, Takada H, Okada S, Yamashita M, Yeh TW, Nishikomori R, Takagi M, Imai K, Ochs HD, Morio T
Allergol Int 2018 Jan;67(1):43-54. Epub 2017 Jul 3 doi: 10.1016/j.alit.2017.06.003. PMID: 28684198
Suri D, Rawat A, Singh S
Indian J Pediatr 2016 Apr;83(4):331-7. Epub 2016 Feb 24 doi: 10.1007/s12098-015-2024-8. PMID: 26909497
Bearden D, Collett M, Quan PL, Costa-Carvalho BT, Sullivan KE
J Allergy Clin Immunol Pract 2016 Nov-Dec;4(6):1059-1065. Epub 2016 Feb 13 doi: 10.1016/j.jaip.2015.12.015. PMID: 26883540

Therapy

Altman K, Zhou C, Hernandez-Trujillo V, Scalchunes C, Rawlings DJ, de la Morena MT
J Clin Immunol 2022 May;42(4):811-818. Epub 2022 Mar 14 doi: 10.1007/s10875-022-01222-8. PMID: 35284987
Qing-Qi R, Ya-Wen L, Huan C, Yu Z, Yun-Fei A, Xue-Mei T, Xiao-Dong Z, Zhi-Yong Z
Clin Rheumatol 2022 Jun;41(6):1889-1897. Epub 2022 Feb 16 doi: 10.1007/s10067-022-06095-1. PMID: 35171366
Madathil Govindaraj G, Jain A, Edavazhippurath A, Bhoyar RC, Dhanasooraj D, Mishra A, Gupta V, Nair M, Shiny PM, Uppuluri R, Kumar A, Kashyap A, Ajith Kumar VT, Shankaran G, Senthivel V, Imran M, Kumar Divakar M, Sawant S, Dalvi A, Madkaikar M, Raj R, Sivasubbu S, Scaria V
Hum Immunol 2022 Apr;83(4):335-345. Epub 2022 Jan 21 doi: 10.1016/j.humimm.2022.01.003. PMID: 35074268
Pal Singh S, Dammeijer F, Hendriks RW
Mol Cancer 2018 Feb 19;17(1):57. doi: 10.1186/s12943-018-0779-z. PMID: 29455639Free PMC Article
Chinen J, Shearer WT
J Allergy Clin Immunol 2003 Mar;111(3 Suppl):S813-8. doi: 10.1067/mai.2003.154. PMID: 12618748

Prognosis

Cardenas-Morales M, Hernandez-Trujillo VP
Clin Rev Allergy Immunol 2022 Aug;63(1):22-35. Epub 2021 Jul 9 doi: 10.1007/s12016-021-08870-5. PMID: 34241796Free PMC Article
Rijkers GT, Holzer L, Dusselier T
Curr Opin Pulm Med 2019 May;25(3):323-329. doi: 10.1097/MCP.0000000000000580. PMID: 30920458
Mazza JM, Lin SY
Int Forum Allergy Rhinol 2016 Oct;6(10):1029-1033. Epub 2016 May 17 doi: 10.1002/alr.21789. PMID: 27187624
Staines Boone AT, Torres Martínez MG, López Herrera G, de Leija Portilla JO, Espinosa Padilla SE, Espinosa Rosales FJ, Lugo Reyes SO
J Clin Immunol 2014 Feb;34(2):134-7. Epub 2013 Dec 12 doi: 10.1007/s10875-013-9971-5. PMID: 24338562
Ochs HD, Smith CI
Medicine (Baltimore) 1996 Nov;75(6):287-99. doi: 10.1097/00005792-199611000-00001. PMID: 8982147

Clinical prediction guides

Cardenas-Morales M, Hernandez-Trujillo VP
Clin Rev Allergy Immunol 2022 Aug;63(1):22-35. Epub 2021 Jul 9 doi: 10.1007/s12016-021-08870-5. PMID: 34241796Free PMC Article
Smith CIE, Burger JA
Front Immunol 2021;12:689472. Epub 2021 Jun 10 doi: 10.3389/fimmu.2021.689472. PMID: 34177947Free PMC Article
Busygina K, Denzinger V, Bernlochner I, Weber C, Lorenz R, Siess W
Thromb Haemost 2019 Aug;119(8):1212-1221. Epub 2019 May 14 doi: 10.1055/s-0039-1687877. PMID: 31087308
van de Veerdonk FL, Lauwerys B, Marijnissen RJ, Timmermans K, Di Padova F, Koenders MI, Gutierrez-Roelens I, Durez P, Netea MG, van der Meer JW, van den Berg WB, Joosten LA
Arthritis Rheum 2011 Jun;63(6):1507-16. doi: 10.1002/art.30314. PMID: 21400475
Tonnelle C, Cuisinier AM, Gauthier L, Guelpa-Fonlupt V, Milili M, Schiff C, Fougereau M
Ann N Y Acad Sci 1995 Sep 29;764:231-41. doi: 10.1111/j.1749-6632.1995.tb55833.x. PMID: 7486530

Recent systematic reviews

Drzymalla E, Green RF, Knuth M, Khoury MJ, Dotson WD, Gundlapalli A
Clin Immunol 2022 Oct;243:109097. Epub 2022 Aug 13 doi: 10.1016/j.clim.2022.109097. PMID: 35973637Free PMC Article
Khan F, Person H, Dekio F, Ogawa M, Ho HE, Dunkin D, Secord E, Cunningham-Rundles C, Ward SC
J Allergy Clin Immunol Pract 2021 Sep;9(9):3466-3478. Epub 2021 May 21 doi: 10.1016/j.jaip.2021.04.070. PMID: 34029777Free PMC Article
Mazza JM, Lin SY
Int Forum Allergy Rhinol 2016 Oct;6(10):1029-1033. Epub 2016 May 17 doi: 10.1002/alr.21789. PMID: 27187624

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