Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.


Vivian P Hernandez-Trujillo, MD
Section Editor
Jennifer M Puck, MD
Deputy Editor
Elizabeth TePas, MD, MS


Immunoglobulins are produced by plasma cells, which themselves are the result of the development and differentiation of B cells. 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). Primary agammaglobulinemia is most commonly inherited as an X-linked trait, but autosomal-recessive (AR) forms have also been reported. Only those inherited defects that are intrinsic to and limited to cells of the B cell lineage will be considered in this topic.

The following related issues are discussed separately:

Other primary immunodeficiency diseases that have agammaglobulinemia or hypogammaglobulinemia associated with combined B and T cell defects and therefore are part of a broader immunodeficiency (see "Severe combined immunodeficiency (SCID): An overview" and "T-B-NK+ SCID: Pathogenesis and genetics" and "Syndromic immunodeficiencies")

Hypogammaglobulinemia that is secondary to extrinsic factors, such as malignancy, medications, and excessive loss of immunoglobulin (see "Secondary immunodeficiency due to underlying disease states, environmental exposures, and miscellaneous causes")

The various causes of hypogammaglobulinemia (see "Primary humoral immunodeficiencies: An overview" and "Transient hypogammaglobulinemia of infancy" and "IgG subclass deficiency" and "Specific antibody deficiency" and "IgG subclasses: Physical properties, genetics, and biologic functions" and "Pathogenesis of common variable immunodeficiency")

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: Nov 30, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
  1. Ochs HD, Smith CI. X-linked agammaglobulinemia. A clinical and molecular analysis. Medicine (Baltimore) 1996; 75:287.
  2. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol 2000; 19:183.
  3. Ochs HD, Stiehm ER, Winkelstein JA. Antibody deficiencies. In: Immmunologic disorders in infants and children, 5th ed, Stiehm ER, Ochs HD, Winkelstein JA (Eds), Elsevier/Sanders, Philadelphia 2004. p.356.
  4. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993; 72:279.
  5. Vetrie D, Vorechovský I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361:226.
  6. Winkelstein JA, Marino MC, Lederman HM, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006; 85:193.
  7. BRUTON OC. Agammaglobulinemia. Pediatrics 1952; 9:722.
  8. Lindvall JM, Blomberg KE, Väliaho J, et al. Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Immunol Rev 2005; 203:200.
  9. Conley ME, Broides A, Hernandez-Trujillo V, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev 2005; 203:216.
  10. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine (Baltimore) 1985; 64:145.
  11. Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol 2002; 104:221.
  12. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr 2002; 141:566.
  13. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 1993; 86:31.
  14. Morales-Aza B, Glennie SJ, Garcez TP, et al. Impaired maintenance of naturally acquired T-cell memory to the meningococcus in patients with B-cell immunodeficiency. Blood 2009; 113:4206.
  15. Ramesh M, Simchoni N, Hamm D, Cunningham-Rundles C. High-throughput sequencing reveals an altered T cell repertoire in X-linked agammaglobulinemia. Clin Immunol 2015; 161:190.
  16. Hashimoto S, Miyawaki T, Futatani T, et al. Atypical X-linked agammaglobulinemia diagnosed in three adults. Intern Med 1999; 38:722.
  17. Kornfeld SJ, Haire RN, Strong SJ, et al. Extreme variation in X-linked agammaglobulinemia phenotype in a three-generation family. J Allergy Clin Immunol 1997; 100:702.
  18. Morwood K, Bourne H, Gold M, et al. Phenotypic variability: clinical presentation between the 6th year and the 60th year in a family with X-linked agammaglobulinemia. J Allergy Clin Immunol 2004; 113:783.
  19. Sarpong S, Skolnick HS, Ochs HD, et al. Survival of wild polio by a patient with XLA. Ann Allergy Asthma Immunol 2002; 88:59.
  20. Stewart DM, Tian L, Nelson DL. A case of X-linked agammaglobulinemia diagnosed in adulthood. Clin Immunol 2001; 99:94.
  21. Usui K, Sasahara Y, Tazawa R, et al. Recurrent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults. Respir Res 2001; 2:188.
  22. Vancikova Z, Freiberger T, Vach W, et al. X-linked agammaglobulinemia in community-acquired pneumonia cases revealed by immunoglobulin level screening at hospital admission. Klin Padiatr 2013; 225:339.
  23. Quartier P, Debré M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 1999; 134:589.
  24. Howard V, Greene JM, Pahwa S, et al. The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol 2006; 118:201.
  25. Tarzi MD, Grigoriadou S, Carr SB, et al. Clinical immunology review series: An approach to the management of pulmonary disease in primary antibody deficiency. Clin Exp Immunol 2009; 155:147.
  26. Cuccherini B, Chua K, Gill V, et al. Bacteremia and skin/bone infections in two patients with X-linked agammaglobulinemia caused by an unusual organism related to Flexispira/Helicobacter species. Clin Immunol 2000; 97:121.
  27. Han S, Schindel C, Genitsariotis R, et al. Identification of a unique Helicobacter species by 16S rRNA gene analysis in an abdominal abscess from a patient with X-linked hypogammaglobulinemia. J Clin Microbiol 2000; 38:2740.
  28. Weir S, Cuccherini B, Whitney AM, et al. Recurrent bacteremia caused by a "Flexispira"-like organism in a patient with X-linked (Bruton's) agammaglobulinemia. J Clin Microbiol 1999; 37:2439.
  29. Simons E, Spacek LA, Lederman HM, Winkelstein JA. Helicobacter cinaedi bacteremia presenting as macules in an afebrile patient with X-linked agammaglobulinemia. Infection 2004; 32:367.
  30. Wilfert CM, Buckley RH, Mohanakumar T, et al. Persistent and fatal central-nervous-system ECHOvirus infections in patients with agammaglobulinemia. N Engl J Med 1977; 296:1485.
  31. Halliday E, Winkelstein J, Webster AD. Enteroviral infections in primary immunodeficiency (PID): a survey of morbidity and mortality. J Infect 2003; 46:1.
  32. Bardelas JA, Winkelstein JA, Seto DS, et al. Fatal ECHO 24 infection in a patient with hypogammaglobulinemia: relationship to dermatomyositis-like syndrome. J Pediatr 1977; 90:396.
  33. Bearden D, Collett M, Quan PL, et al. Enteroviruses in X-Linked Agammaglobulinemia: Update on Epidemiology and Therapy. J Allergy Clin Immunol Pract 2016; 4:1059.
  34. Dittrich AM, Schulze I, Magdorf K, et al. X-linked agammaglobulinaemia and Pneumocystis carinii pneumonia--an unusual coincidence? Eur J Pediatr 2003; 162:432.
  35. Alibrahim A, Lepore M, Lierl M, et al. Pneumocystis carinii pneumonia in an infant with X-linked agammaglobulinemia. J Allergy Clin Immunol 1998; 101:552.
  36. Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol 2009; 124:658.
  37. Wright PF, Hatch MH, Kasselberg AG, et al. Vaccine-associated poliomyelitis in a child with sex-linked agammaglobulinemia. J Pediatr 1977; 91:408.
  38. Gompels MM, Hodges E, Lock RJ, et al. Lymphoproliferative disease in antibody deficiency: a multi-centre study. Clin Exp Immunol 2003; 134:314.
  39. Lavilla P, Gil A, Rodríguez MC, et al. X-linked agammaglobulinemia and gastric adenocarcinoma. Cancer 1993; 72:1528.
  40. Bachmeyer C, Monge M, Cazier A, et al. Gastric adenocarcinoma in a patient with X-linked agammaglobulinaemia. Eur J Gastroenterol Hepatol 2000; 12:1033.
  41. van der Meer JW, Weening RS, Schellekens PT, et al. Colorectal cancer in patients with X-linked agammaglobulinaemia. Lancet 1993; 341:1439.
  42. Brosens LA, Tytgat KM, Morsink FH, et al. Multiple colorectal neoplasms in X-linked agammaglobulinemia. Clin Gastroenterol Hepatol 2008; 6:115.
  43. Echave-Sustaeta JM, Villena V, Verdugo M, et al. X-linked agammaglobulinaemia and squamous lung cancer. Eur Respir J 2001; 17:570.
  44. Maarschalk-Ellerbroek LJ, Oldenburg B, Mombers IM, et al. Outcome of screening endoscopy in common variable immunodeficiency disorder and X-linked agammaglobulinemia. Endoscopy 2013; 45:320.
  45. Conley ME. Are patients with X-linked agammaglobulinemia at increased risk of developing acute lymphoblastic leukemia? J Clin Immunol 2015; 35:98.
  46. Hoshino A, Okuno Y, Migita M, et al. X-linked agammaglobulinemia associated with B-precursor acute lymphoblastic leukemia. J Clin Immunol 2015; 35:108.
  47. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J Clin Immunol 2014; 34:627.
  48. Berlucchi M, Soresina A, Redaelli De Zinis LO, et al. Sensorineural hearing loss in primary antibody deficiency disorders. J Pediatr 2008; 153:293.
  49. Hunter HL, McKenna KE, Edgar JD. Eczema and X-linked agammaglobulinaemia. Clin Exp Dermatol 2008; 33:148.
  50. Saffran DC, Parolini O, Fitch-Hilgenberg ME, et al. Brief report: a point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med 1994; 330:1488.
  51. Kornfeld SJ, Haire RN, Strong SJ, et al. A novel mutation (Cys145-->Stop) in Bruton's tyrosine kinase is associated with newly diagnosed X-linked agammaglobulinemia in a 51-year-old male. Mol Med 1996; 2:619.
  52. Kornfeld SJ, Kratz J, Haire RN, et al. X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol 1995; 95:915.
  53. Wood PM, Mayne A, Joyce H, et al. A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency. J Pediatr 2001; 139:148.
  54. Cham B, Bonilla MA, Winkelstein J. Neutropenia associated with primary immunodeficiency syndromes. Semin Hematol 2002; 39:107.
  55. Farrar JE, Rohrer J, Conley ME. Neutropenia in X-linked agammaglobulinemia. Clin Immunol Immunopathol 1996; 81:271.
  56. Kanegane H, Taneichi H, Nomura K, et al. Severe neutropenia in Japanese patients with x-linked agammaglobulinemia. J Clin Immunol 2005; 25:491.
  57. Plo Rodríguez F, García Rodríguez MC, Ferreira Cerdán A, Fontán Casariego G. [Neutropenia as early manifestation of X-linked agammaglobulinemia. Report on 4 patients]. An Esp Pediatr 1999; 51:235.
  58. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999; 93:190.
  59. Nakagawa N, Imai K, Kanegane H, et al. Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects. J Allergy Clin Immunol 2011; 128:223.
  60. Borte S, von Döbeln U, Fasth A, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood 2012; 119:2552.
  61. de Felipe B, Olbrich P, Lucenas JM, et al. Prospective neonatal screening for severe T- and B-lymphocyte deficiencies in Seville. Pediatr Allergy Immunol 2016; 27:70.
  62. Zhu Q, Zhang M, Rawlings DJ, et al. Deletion within the Src homology domain 3 of Bruton's tyrosine kinase resulting in X-linked agammaglobulinemia (XLA). J Exp Med 1994; 180:461.
  63. Guioli S, Arveiler B, Bardoni B, et al. Close linkage of probe p212 (DXS178) to X-linked agammaglobulinemia. Hum Genet 1989; 84:19.
  64. Kwan SP, Walker AP, Hagemann T, et al. A new RFLP marker, SP282, at the btk locus for genetic analysis in X-linked agammaglobulinaemia families. Prenat Diagn 1994; 14:493.
  65. Parolini O, Hejtmancik JF, Allen RC, et al. Linkage analysis and physical mapping near the gene for X-linked agammaglobulinemia at Xq22. Genomics 1993; 15:342.
  66. Winkelstein JA, Fearon E. Carrier detection of the X-linked primary immunodeficiency diseases using X-chromosome inactivation analysis. J Allergy Clin Immunol 1990; 85:1090.
  67. Fearon ER, Winkelstein JA, Civin CI, et al. Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. N Engl J Med 1987; 316:427.
  68. Conley ME, Puck JM. Carrier detection in typical and atypical X-linked agammaglobulinemia. J Pediatr 1988; 112:688.
  69. Kanegane H, Futatani T, Wang Y, et al. Clinical and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment combined with genetic analysis. J Allergy Clin Immunol 2001; 108:1012.
  70. Liese JG, Wintergerst U, Tympner KD, Belohradsky BH. High- vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia. Am J Dis Child 1992; 146:335.
  71. Sweinberg SK, Wodell RA, Grodofsky MP, et al. Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy Clin Immunol 1991; 88:96.
  72. Barnes S, Kotecha S, Douglass JA, et al. Evolving practice: X-linked agammaglobulinemia and lung transplantation. Am J Transplant 2015; 15:1110.
  73. Abu-Arja RF, Chernin LR, Abusin G, et al. Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia. Pediatr Blood Cancer 2015; 62:1674.
  74. Ikegame K, Imai K, Yamashita M, et al. Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity. J Hematol Oncol 2016; 9:9.
  75. Winkelstein JA, Conley ME, James C, et al. Adults with X-linked agammaglobulinemia: impact of disease on daily lives, quality of life, educational and socioeconomic status, knowledge of inheritance, and reproductive attitudes. Medicine (Baltimore) 2008; 87:253.
  76. Minegishi Y, Coustan-Smith E, Wang YH, et al. Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia. J Exp Med 1998; 187:71.
  77. Minegishi Y, Coustan-Smith E, Rapalus L, et al. Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J Clin Invest 1999; 104:1115.
  78. Minegishi Y, Rohrer J, Coustan-Smith E, et al. An essential role for BLNK in human B cell development. Science 1999; 286:1954.
  79. Conley ME, Rohrer J, Rapalus L, et al. Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol Rev 2000; 178:75.
  80. Yel L, Minegishi Y, Coustan-Smith E, et al. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N Engl J Med 1996; 335:1486.
  81. Ferrari S, Lougaris V, Caraffi S, et al. Mutations of the Igbeta gene cause agammaglobulinemia in man. J Exp Med 2007; 204:2047.
  82. Conley ME, Farmer DM, Dobbs AK, et al. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin Exp Immunol 2008; 152:39.
  83. Cliffe ST, Bloch DB, Suryani S, et al. Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome. J Allergy Clin Immunol 2012; 130:735.
  84. Conley ME, Dobbs AK, Quintana AM, et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J Exp Med 2012; 209:463.
  85. Conley ME, Dobbs AK, Farmer DM, et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 2009; 27:199.
  86. Gemayel KT, Litman GW, Sriaroon P. Autosomal recessive agammaglobulinemia associated with an IGLL1 gene missense mutation. Ann Allergy Asthma Immunol 2016; 117:439.
  87. Khalili A, Plebani A, Vitali M, et al. Autosomal recessive agammaglobulinemia: a novel non-sense mutation in CD79a. J Clin Immunol 2014; 34:138.
  88. Lougaris V, Vitali M, Baronio M, et al. Autosomal recessive agammaglobulinemia: the third case of Igβ deficiency due to a novel non-sense mutation. J Clin Immunol 2014; 34:425.
  89. Kubota K, Kim JY, Sawada A, et al. LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins. FEBS Lett 2004; 564:147.
  90. Boisson B, Wang YD, Bosompem A, et al. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells. J Clin Invest 2013; 123:4781.