Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

IgG subclass deficiency

Alan P Knutsen, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Anna M Feldweg, MD


The clinical presentation, pathogenesis, diagnosis, and treatment of immunoglobulin G (IgG) subclass deficiency are presented here. The physical and biologic properties of IgG subclasses are reviewed separately. (See "IgG subclasses: Physical properties, genetics, and biologic functions".)


The term "IgG subclass deficiency" refers to a significant decrease in the serum concentrations of one or more subclasses of IgG in a patient whose total IgG concentration is normal [1].

Clinically significant deficiency — IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.

Lower limits of normal — The normal ranges for IgG subclasses are broad and vary with the age of the population studied, presence or absence of disease, and the method of analysis (table 1) [2-9].

For children 4 to 10 years of age, levels below the following are considered abnormal:

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: Nov 2017. | This topic last updated: Feb 27, 2017.
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 ©2017 UpToDate, Inc.
  1. Herrod HG. Clinical significance of IgG subclasses. Curr Opin Pediatr 1993; 5:696.
  2. Hanson LA, Söderström R, Avanzini A, et al. Immunoglobulin subclass deficiency. Pediatr Infect Dis J 1988; 7:S17.
  3. Söderström T, Söderström R, Avanzini A, et al. Immunoglobulin G subclass deficiencies. Int Arch Allergy Appl Immunol 1987; 82:476.
  4. Oxelius VA, Hanson LA, Björkander J, et al. IgG3 deficiency: common in obstructive lung disease. Hereditary in families with immunodeficiency and autoimmune disease. Monogr Allergy 1986; 20:106.
  5. Aucouturier P, Lacombe C, Bremard C, et al. Serum IgG subclass levels in patients with primary immunodeficiency syndromes or abnormal susceptibility to infections. Clin Immunol Immunopathol 1989; 51:22.
  6. Björkander J, Bengtsson U, Oxelius VA, Hanson LA. Symptoms in patients with lowered levels of IgG subclasses, with or without IgA deficiency, and effects of immunoglobulin prophylaxis. Monogr Allergy 1986; 20:157.
  7. Migone N, Oliviero S, de Lange G, et al. Multiple gene deletions within the human immunoglobulin heavy-chain cluster. Proc Natl Acad Sci U S A 1984; 81:5811.
  8. Nahm MH, Macke K, Kwon OH, et al. Immunologic and clinical status of blood donors with subnormal levels of IgG2. J Allergy Clin Immunol 1990; 85:769.
  9. Aucouturier P, Mariault M, Lacombe C, Preud'homme JL. Frequency of selective IgG subclass deficiency: a reappraisal. Clin Immunol Immunopathol 1992; 63:289.
  10. Ochs HD, Stiehm ER, Winkelstein JA, et al. Antibody deficiencies. In: Immunologic disorders in infants and children, 5th ed, Ochs HD, Stiehm ER, Winkelstein JA (Eds), Elsevier, Philadelphia 2004.
  11. Meulenbroek AJ, Zeijlemaker WP. Human IgG subclasses: Useful diagnostic markers for immunocompetence, 2nd edition, CLB, Amsterdam, The Netherlands 2000.
  12. Karaca NE, Karadeniz C, Aksu G, Kutukculer N. Clinical and laboratory evaluation of periodically monitored Turkish children with IgG subclass deficiencies. Asian Pac J Allergy Immunol 2009; 27:43.
  13. Rabbani H, Kondo N, Smith CI, Hammarström L. The influence of gene deletions and duplications within the IGHC locus on serum immunoglobulin subclass levels. Clin Immunol Immunopathol 1995; 76:S214.
  14. Pan Q, Hammarström L. Molecular basis of IgG subclass deficiency. Immunol Rev 2000; 178:99.
  15. Plebani A, Carbonara AO, Bottaro A, et al. Gene deletion as a cause of associated deficiency of IgA1, IgG2, IgG4 and IgE. Immunodeficiency 1993; 4:245.
  16. Carbonara AO, Demarchi M. Ig isotypes deficiency caused by gene deletions. Monogr Allergy 1986; 20:13.
  17. Bottaro A, DeMarchi M, DeLange GG, et al. Human IGHC locus restriction fragment length polymorphisms in IgG4 deficiency: evidence for a structural IGHC defect. Eur J Immunol 1989; 19:2159.
  18. Oxelius VA. Serum IgG and IgG subclass contents in different Gm phenotypes. Scand J Immunol 1993; 37:149.
  19. Oxelius VA. Lack of the G2m(n) allotype in IgG subclass deficiency, in IgG2 deficiency together with lack of G1m(a) and G3m(g), and in IgG3 deficiency together with lack of G1m(f) and G3m(b). Scand J Immunol 1990; 31:243.
  20. Schur PH, Borel H, Gelfand EW, et al. Selective gamma-g globulin deficiencies in patients with recurrent pyogenic infections. N Engl J Med 1970; 283:631.
  21. Shackelford PG, Granoff DM, Madassery JV, et al. Clinical and immunologic characteristics of healthy children with subnormal serum concentrations of IgG2. Pediatr Res 1990; 27:16.
  22. Oxelius VA. Chronic infections in a family with hereditary deficiency of IgG2 and IgG4. Clin Exp Immunol 1974; 17:19.
  23. Lefranc MP, Lefranc G, Rabbitts TH. Inherited deletion of immunoglobulin heavy chain constant region genes in normal human individuals. Nature 1982; 300:760.
  24. Hammarström L, Smith CI. IgG2 deficiency in a healthy blood donor. Concomitant lack of IgG2, IgA and IgE immunoglobulins and specific anti-carbohydrate antibodies. Clin Exp Immunol 1983; 51:600.
  25. Morgan G, Levinsky RJ. Clinical significance of IgG subclass deficiency. Arch Dis Child 1988; 63:771.
  26. Umetsu DT, Ambrosino DM, Quinti I, et al. Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency. N Engl J Med 1985; 313:1247.
  27. Lawton AR. IgG subclass deficiency and the day-care generation. Pediatr Infect Dis J 1999; 18:462.
  28. Hill SL, Mitchell JL, Burnett D, Stockley RA. IgG subclasses in the serum and sputum from patients with bronchiectasis. Thorax 1998; 53:463.
  29. Lefranc MP, Hammarström L, Smith CI, Lefranc G. Gene deletions in the human immunoglobulin heavy chain constant region locus: molecular and immunological analysis. Immunodefic Rev 1991; 2:265.
  30. Hammarström L, Carbonara AO, DeMarchi M, et al. Generation of the antibody repertoire in individuals with multiple immunoglobulin heavy chain constant region gene deletions. Scand J Immunol 1987; 25:189.
  31. Plebani A, Ugazio AG, Meini A, et al. Extensive deletion of immunoglobulin heavy chain constant region genes in the absence of recurrent infections: when is IgG subclass deficiency clinically relevant? Clin Immunol Immunopathol 1993; 68:46.
  32. Depiero A, Kaminski DA, Halsey JF, et al. Immunologic compensation in a patient with a large IgH constant region deletion. J Allergy Clin Immunol 2001; 107:1051.
  33. Ambrosino DM, Umetsu DT, Siber GR, et al. Selective defect in the antibody response to Haemophilus influenzae type b in children with recurrent infections and normal serum IgG subclass levels. J Allergy Clin Immunol 1988; 81:1175.
  34. Schwitzguébel AJ, Jandus P, Lacroix JS, et al. Immunoglobulin deficiency in patients with chronic rhinosinusitis: Systematic review of the literature and meta-analysis. J Allergy Clin Immunol 2015; 136:1523.
  35. Yount WJ, Seligmann M, Hong R, et al. Imbalances of gamma globulin subgroups and gene defects in patients with primary hypogammaglobulinemia. J Clin Invest 1970; 49:1957.
  36. Oxelius VA, Laurell AB, Lindquist B, et al. IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency. N Engl J Med 1981; 304:1476.
  37. Plebani A, Monafo V, Avanzini MA, et al. Relationship between IgA and IgG subclass deficiencies: a reappraisal. Monogr Allergy 1986; 20:171.
  38. Oxelius VA, Berkel AI, Hanson LA. IgG2 deficiency in ataxia-telangiectasia. N Engl J Med 1982; 306:515.
  39. Yel L, Ramanuja S, Gupta S. Clinical and immunological features in IgM deficiency. Int Arch Allergy Immunol 2009; 150:291.
  40. de Moraes Lui C, Oliveira LC, Diogo CL, et al. Immunoglobulin G subclass concentrations and infections in children and adolescents with severe asthma. Pediatr Allergy Immunol 2002; 13:195.
  41. Wolpert J, Knutsen AP. Natural history of selective antibody deficiency to bacterial polysaccharide antigens in children. Pediatr Asthma Allergy Immunol 1998; 12:183.
  42. Kim JH, Park S, Hwang YI, et al. Immunoglobulin G Subclass Deficiencies in Adult Patients with Chronic Airway Diseases. J Korean Med Sci 2016; 31:1560.
  43. Bussel J, Morell A, Skvaril F. IgG2 deficiency in autoimmune cytopenias. Monogr Allergy 1986; 20:116.
  44. Bremard-Oury C, Aucouturier P, Debré M, et al. Immunoglobulin G subclasses in patients with immunodeficiencies. Monogr Allergy 1986; 20:75.
  45. Lacombe C, Aucouturier P, Preud'homme JL. Selective IgG1 deficiency. Clin Immunol Immunopathol 1997; 84:194.
  46. Javier FC 3rd, Moore CM, Sorensen RU. Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital. Ann Allergy Asthma Immunol 2000; 84:25.
  47. Braconier JH, Nilsson B, Oxelius VA, Karup-Pedersen F. Recurrent pneumococcal infections in a patient with lack of specific IgG and IgM pneumococcal antibodies and deficiency of serum IgA, IgG2 and IgG4. Scand J Infect Dis 1984; 16:407.
  48. Siber GR, Schur PH, Aisenberg AC, et al. Correlation between serum IgG-2 concentrations and the antibody response to bacterial polysaccharide antigens. N Engl J Med 1980; 303:178.
  49. Hammarström L, Smith CI. IgG subclasses in bacterial infections. Monogr Allergy 1986; 19:122.
  50. Bass JL, Nuss R, Mehta KA, et al. Recurrent meningococcemia associated with IgG2-subclass deficiency. N Engl J Med 1983; 309:430.
  51. Escobar-Pérez X, Dorta-Contreras AJ, Interián-Morales MT, et al. IgG2 immunodeficiency: association to pediatric patients with bacterial meningoencephalitis. Arq Neuropsiquiatr 2000; 58:141.
  52. O'Keeffe S, Finnegan P. IgG subclass deficiency. Chest 1993; 104:1940.
  53. Oxelius VA. Immunoglobulin G (IgG) subclasses and human disease. Am J Med 1984; 76:7.
  54. Eriksson P, Almroth G, Denneberg T, Lindström FD. IgG2 deficiency in primary Sjögren's syndrome and hypergammaglobulinemic purpura. Clin Immunol Immunopathol 1994; 70:60.
  55. Jiménez A, López-Trascasa M, Fontán G. Incidence of selective IgG2 deficiency in patients with vasculitis. Clin Exp Immunol 1989; 78:149.
  56. Inoue R, Kondo N, Kobayashi Y, et al. IgG2 deficiency associated with defects in production of interferon-gamma; comparison with common variable immunodeficiency. Scand J Immunol 1995; 41:130.
  57. Kalfa VC, Roberts RL, Stiehm ER. The syndrome of chronic mucocutaneous candidiasis with selective antibody deficiency. Ann Allergy Asthma Immunol 2003; 90:259.
  58. Lotz DR, Knutsen AP. Concomitant selective antibody deficiency in pediatric patients with mannose-binding lectin deficiency. Pediatric Allergy, Immunology, and Pulmonology 2010; 23:265.
  59. Parkin JM, Helbert M, Hughes CL, Pinching AJ. Immunoglobulin G subclass deficiency and susceptibility to pyogenic infections in patients with AIDS-related complex and AIDS. AIDS 1989; 3:37.
  60. Aucouturier P, Barra A, Intrator L, et al. Long lasting IgG subclass and antibacterial polysaccharide antibody deficiency after allogeneic bone marrow transplantation. Blood 1987; 70:779.
  61. Chan JF, To KK, Tse H, et al. The lower serum immunoglobulin G2 level in severe cases than in mild cases of pandemic H1N1 2009 influenza is associated with cytokine dysregulation. Clin Vaccine Immunol 2011; 18:305.
  62. Zenone T, Souquet PJ, Cunningham-Rundles C, Bernard JP. Hodgkin's disease associated with IgA and IgG subclass deficiency. J Intern Med 1996; 240:99.
  63. Garside JP, Kerrin DP, Brownlee KG, et al. Immunoglobulin and IgG subclass levels in a regional pediatric cystic fibrosis clinic. Pediatr Pulmonol 2005; 39:135.
  64. De Gracia J, Rodrigo MJ, Morell F, et al. IgG subclass deficiencies associated with bronchiectasis. Am J Respir Crit Care Med 1996; 153:650.
  65. Wilson NW, Daaboul J, Bastian JF. Association of autoimmunity with IgG2 and IgG4 subclass deficiency in a growth hormone-deficient child. J Clin Immunol 1990; 10:330.
  66. Ojuawo A, Milla PJ, Lindley KJ. Serum immunoglobulin and immunoglobulin G subclasses in children with allergic colitis. West Afr J Med 1998; 17:206.
  67. Caksen H, Oner AF, Arslan S, et al. Immunoglobulin subgroups in children with febrile seizures. Pediatr Int 2001; 43:58.
  68. Lenti C, Masserini C, Barlocco A, et al. IgG2 deficiency in children with febrile convulsions: a familial study. Ital J Neurol Sci 1993; 14:561.
  69. Schatorjé EJ, de Jong E, van Hout RW, et al. The Challenge of Immunoglobulin-G Subclass Deficiency and Specific Polysaccharide Antibody Deficiency--a Dutch Pediatric Cohort Study. J Clin Immunol 2016; 36:141.
  70. Knutsen AP, Becker BA. Evolution of IgG subclass deficiency into common variable immunodeficiency in a child with pulmonary interstitial glycogenosis. Pediatr Asthma Allergy Immunol 2009; 21:191.
  71. Oxelius VA. IgG subclass pattern in primary immunodeficiency disorders. Monogr Allergy 1986; 19:156.
  72. Abrahamian F, Agrawal S, Gupta S. Immunological and clinical profile of adult patients with selective immunoglobulin subclass deficiency: response to intravenous immunoglobulin therapy. Clin Exp Immunol 2010; 159:344.
  73. Barton JC, Bertoli LF, Barton JC, Acton RT. Selective subnormal IgG3 in 121 adult index patients with frequent or severe bacterial respiratory tract infections. Cell Immunol 2016; 299:50.
  74. Snowden JA, Milford-Ward A, Cookson LJ, McKendrick MW. Recurrent lymphocytic meningitis associated with hereditary isolated IgG subclass 3 deficiency. J Infect 1993; 27:285.
  75. Heiner DC, Myers A, Beck CS. Deficiency of IgG4: a disorder associated with frequent infections and bronchiectasis that may be familial. Clin Rev Allergy 1983; 1:259.
  76. Bartmann P, Kleihauer E. Undetectable IgG4 in immunoprecipitation: association with repeated infections in children? Eur J Pediatr 1988; 148:211.
  77. Moss RB, Carmack MA, Esrig S. Deficiency of IgG4 in children: association of isolated IgG4 deficiency with recurrent respiratory tract infection. J Pediatr 1992; 120:16.
  78. Annerén G, Magnusson CG, Lilja G, Nordvall SL. Abnormal serum IgG subclass pattern in children with Down's syndrome. Arch Dis Child 1992; 67:628.
  79. Hamilton RG. Human IgG subclass measurements in the clinical laboratory. Clin Chem 1987; 33:1707.
  80. Bossuyt X, Mariën G, Meyts I, et al. Determination of IgG subclasses: a need for standardization. J Allergy Clin Immunol 2005; 115:872.
  81. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol 2015; 136:1186.
  82. Klaustermeyer WB, Gianos ME, Kurohara ML, et al. IgG subclass deficiency associated with corticosteroids in obstructive lung disease. Chest 1992; 102:1137.
  83. Leickly FE, Buckley RH. Development of IgA and IgG2 subclass deficiency after sulfasalazine therapy. J Pediatr 1986; 108:481.
  84. Maeoka Y, Hara T, Dejima S, Takeshita K. IgA and IgG2 deficiency associated with zonisamide therapy: a case report. Epilepsia 1997; 38:611.
  85. Ishizaka A, Nakanishi M, Kasahara E, et al. Phenytoin-induced IgG2 and IgG4 deficiencies in a patient with epilepsy. Acta Paediatr 1992; 81:646.
  86. Kato Z, Watanabe M, Kondo N. IgG2, IgG4 and IgA deficiency possibly associated with carbamazepine treatment. Eur J Pediatr 2003; 162:209.
  87. Qvarfordt I, Riise GC, Andersson BA, Larsson S. IgG subclasses in smokers with chronic bronchitis and recurrent exacerbations. Thorax 2001; 56:445.
  88. Sorensen RU, Leiva LE, Giangrosso PA, et al. Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine. Pediatr Infect Dis J 1998; 17:685.
  89. Briere EC, Rubin L, Moro PL, et al. Prevention and control of haemophilus influenzae type b disease: recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep 2014; 63:1.
  90. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014; 58:e44.
  91. Gutiérrez-Tarango MD, Berber A. Safety and efficacy of two courses of OM-85 BV in the prevention of respiratory tract infections in children during 12 months. Chest 2001; 119:1742.
  92. Buckley RH. Immunoglobulin G subclass deficiency: fact or fancy? Curr Allergy Asthma Rep 2002; 2:356.
  93. Abdou NI, Greenwell CA, Mehta R, et al. Efficacy of intravenous gammaglobulin for immunoglobulin G subclass and/or antibody deficiency in adults. Int Arch Allergy Immunol 2009; 149:267.
  94. Shearer WT, Buckley RH, Engler RJ, et al. Practice parameters for the diagnosis and management of immunodeficiency. The Clinical and Laboratory Immunology Committee of the American Academy of Allergy, Asthma, and Immunology (CLIC-AAAAI). Ann Allergy Asthma Immunol 1996; 76:282.
  95. Meyts I, Bossuyt X, Proesmans M, De B. Isolated IgG3 deficiency in children: to treat or not to treat? Case presentation and review of the literature. Pediatr Allergy Immunol 2006; 17:544.
  96. Avanzini MA, Björkander J, Söderström R, et al. Qualitative and quantitative analyses of the antibody response elicited by Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugates in adults with IgG subclass deficiencies and frequent infections. Clin Exp Immunol 1994; 96:54.
  97. Barlan IB, Geha RS, Schneider LC. Therapy for patients with recurrent infections and low serum IgG3 levels. J Allergy Clin Immunol 1993; 92:353.
  98. Olinder-Nielsen AM, Granert C, Forsberg P, et al. Immunoglobulin prophylaxis in 350 adults with IgG subclass deficiency and recurrent respiratory tract infections: a long-term follow-up. Scand J Infect Dis 2007; 39:44.
  99. Ortigas AP, Leiva LE, Moore C, et al. Natural history of specific antibody deficiency after IgG replacement therapy. Ann Allergy Asthma Immunol 1999; 82:71.