UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Transient hypogammaglobulinemia of infancy

Authors
Ilan Dalal, MD
Chaim M Roifman, MD, FRCPC, FCACB
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS

INTRODUCTION

Transient hypogammaglobulinemia of infancy (THI) was classically described as an accentuation and prolongation of the "physiologic" immunoglobulin nadir that is normally observed during the first three to six months of life (figure 1) [1,2]. However, there remains no full agreement among immunologists regarding the definition of THI due to the absence of specific markers or a genetic signature. While some use sweeping inclusion criteria such as a reduction in any immunoglobulin (immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM]), beyond the physiologic nadir [2-7], most agree that low IgG is essential for considering the diagnosis [8-12].

The definition proposed by the International Union of Immunological Societies (IUIS) committee [13] calling for obligatory low IgG and IgA in THI poses multiple challenges. It excludes all cases of isolated, transient low IgG (4 to 45 percent of cases of classically defined THI [3,8,10,14]) and also includes other entities such as hyper-IgM syndrome and common variable immunodeficiency (CVID) [15]. The European Society for Immunodeficiencies (ESID) has proposed the term "unclassified hypogammaglobulinemia" for children in the first three years of life with low IgG levels, reserving THI for those children that recover by age four years [16].

The authors of this topic use a more conservative and balanced definition, which, on one hand, is flexible enough to include most cases historically considered to have THI but sufficiently restrictive to prevent confusion with other possible conditions. It encompasses low serum IgG levels in the presence or absence of low IgA or IgM (consistent with the ESID criteria) and normalization of IgG levels, as well as specific antibodies, over time. Hypogammaglobulinemia associated with a reduction in circulating B cells, abnormal cellular immunity, and syndromic features is excluded from the definition of THI.

It is important to recognize that the diagnosis of THI is made retrospectively. It is one of several possible diagnoses considered in the heterogeneous population of young children presenting with recurrent infections and low immunoglobulins.

This topic reviews the clinical features, diagnosis, and management of THI. Other humoral immune defects are reviewed in greater detail separately. (See "Primary humoral immunodeficiencies: An overview".)

              

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Mon Oct 24 00:00:00 GMT+00:00 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 ©2016 UpToDate, Inc.
References
Top
  1. GITLIN D, JANEWAY CA. Agammaglobulinemia, congenital, acquired and transient forms. Prog Hematol 1956; 1:318.
  2. McGeady SJ. Transient hypogammaglobulinemia of infancy. In: Stiehm's Immune Deficiencies, Stiehm ER. (Ed), Elsevier Limited, Oxford 2014. p.417.
  3. Keles S, Artac H, Kara R, et al. Transient hypogammaglobulinemia and unclassified hypogammaglobulinemia: 'similarities and differences'. Pediatr Allergy Immunol 2010; 21:843.
  4. Tiller TL Jr, Buckley RH. Transient hypogammaglobulinemia of infancy: review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up. J Pediatr 1978; 92:347.
  5. Kiliç SS, Tezcan I, Sanal O, et al. Transient hypogammaglobulinemia of infancy: clinical and immunologic features of 40 new cases. Pediatr Int 2000; 42:647.
  6. Kidon MI, Handzel ZT, Schwartz R, et al. Symptomatic hypogammaglobulinemia in infancy and childhood - clinical outcome and in vitro immune responses. BMC Fam Pract 2004; 5:23.
  7. Whelan MA, Hwan WH, Beausoleil J, et al. Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization. J Clin Immunol 2006; 26:7.
  8. Dalal I, Reid B, Nisbet-Brown E, Roifman CM. The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr 1998; 133:144.
  9. Kowalczyk D, Mytar B, Zembala M. Cytokine production in transient hypogammaglobulinemia and isolated IgA deficiency. J Allergy Clin Immunol 1997; 100:556.
  10. Rutkowska M, Lenart M, Bukowska-Strakovà K, et al. The number of circulating CD4+ CD25high Foxp3+ T lymphocytes is transiently elevated in the early childhood of transient hypogammaglobulinemia of infancy patients. Clin Immunol 2011; 140:307.
  11. Bukowska-Straková K, Kowalczyk D, Baran J, et al. The B-cell compartment in the peripheral blood of children with different types of primary humoral immunodeficiency. Pediatr Res 2009; 66:28.
  12. Cano F, Mayo DR, Ballow M. Absent specific viral antibodies in patients with transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol 1990; 85:510.
  13. Picard C, Al-Herz W, Bousfiha A, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol 2015; 35:696.
  14. Karaca NE, Aksu G, Gulez N, et al. New laboratory findings in Turkish patients with transient hypogammaglobulinemia of infancy. Iran J Allergy Asthma Immunol 2010; 9:237.
  15. Moschese V, Graziani S, Avanzini MA, et al. A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: results from the Italian Primary Immunodeficiency Network. Int J Immunopathol Pharmacol 2008; 21:343.
  16. Moschese V, Cavaliere FM, Graziani S, et al. Decreased IgM, IgA, and IgG response to pneumococcal vaccine in children with transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol 2016; 137:617.
  17. Walker AM, Kemp AS, Hill DJ, Shelton MJ. Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities. Arch Dis Child 1994; 70:183.
  18. Qian JH, Zhu JX, Zhu XD, Chen TX. Clinical features and follow-up of Chinese patients with symptomatic hypogammaglobulinemia in infancy. Chin Med J (Engl) 2009; 122:1877.
  19. Kutukculer N, Gulez N. The outcome of patients with unclassified hypogammaglobulinemia in early childhood. Pediatr Allergy Immunol 2009; 20:693.
  20. McGeady SJ. Transient hypogammaglobulinemia of infancy: need to reconsider name and definition. J Pediatr 1987; 110:47.
  21. Dressler F, Peter HH, Müller W, Rieger CH. Transient hypogammaglobulinemia of infancy: Five new cases, review of the literature and redefinition. Acta Paediatr Scand 1989; 78:767.
  22. Siegel RL, Issekutz T, Schwaber J, et al. Deficiency of T helper cells in transient hypogammaglobulinemia of infancy. N Engl J Med 1981; 305:1307.
  23. FUDENBERG HH, FUDENBERG BR. ANTIBODY TO HEREDITARY HUMAN GAMMA-GLOBULIN (GM) FACTOR RESULTING FROM MATERNAL-FETAL INCOMPATIBILITY. Science 1964; 145:170.
  24. Soothill JF. Immunoglobulins in first-degree relatives of patients with hypogammaglobulinaemia. Transient hypogammaglobulinaemia: a possible manifestation of heterozygocity. Lancet 1968; 1:1001.
  25. Rieger CH, Nelson LA, Peri BA, et al. Transient hypogammaglobulinemia of infancy. J Pediatr 1977; 91:601.
  26. Lentz D, Gershwin ME. Is transient hypogammaglobulinemia of infancy a manifestation of zinc deficiency? Dev Comp Immunol 1984; 8:1.
  27. Rutkowska M, Trzyna E, Lenart M, et al. The elevated number of circulating regulatory T cells in patients with transient hypogammaglobulinemia of infancy is not associated with any abnormalities in the genes encoding the TGF-β receptors. Clin Immunol 2013; 149:83.
  28. Wilson CB, Lewis DB, Penix LA. The physiologic immunodeficiency of immaturity. In: Immunologic disorders in infants and children, Stiehm ER (Ed), WB Saunders, Philadelphia 1996. p.253.
  29. Artac H, Kara R, Gokturk B, Reisli I. Reduced CD19 expression and decreased memory B cell numbers in transient hypogammaglobulinemia of infancy. Clin Exp Med 2013; 13:257.
  30. Dorsey MJ, Orange JS. Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy. Ann Allergy Asthma Immunol 2006; 97:590.
  31. van Zelm MC, Reisli I, van der Burg M, et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006; 354:1901.
  32. Fineman SM, Rosen FS, Geha RS. Transient hypogammaglobulinemia, elevated immunoglobulin E levels, and food allergy. J Allergy Clin Immunol 1979; 64:216.
  33. Sumikawa Y, Kato J, Kan Y, et al. Severe atopic dermatitis associated with transient hypogammaglobulinemia of infancy. Int J Dermatol 2015; 54:e185.
  34. Moschese V, Carsetti R, Graziani S, et al. Memory B-cell subsets as a predictive marker of outcome in hypogammaglobulinemia during infancy. J Allergy Clin Immunol 2007; 120:474.
  35. Alachkar H, Taubenheim N, Haeney MR, et al. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol 2006; 120:310.
  36. Carsetti R, Rosado MM, Donnanno S, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol 2005; 115:412.
  37. Buckley RH. Immunodeficiency diseases. JAMA 1992; 268:2797.
  38. Iseki M, Heiner DC. Immunodeficiency disorders. Pediatr Rev 1993; 14:226.
  39. 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.
  40. Kornfeld SJ, Kratz J, Haire RN, et al. X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol 1995; 95:915.
  41. 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.
  42. Memmedova L, Azarsiz E, Edeer Karaca N, et al. Does intravenous immunoglobulin therapy prolong immunodeficiency in transient hypogammaglobulinemia of infancy? Pediatr Rep 2013; 5:e14.
  43. Rosen FS, Janeway CA. The gamma globulins. 3. The antibody deficiency syndromes. N Engl J Med 1966; 275:769.
  44. Doğu F, Ikincioğullari A, Babacan E. Transient hypogammaglobulinemia of infancy and early childhood: outcome of 30 cases. Turk J Pediatr 2004; 46:120.
  45. Centers for Disease Control and Prevention (CDC). Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October 1993-June 1994. MMWR Morb Mortal Wkly Rep 1994; 43:505.
  46. Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies (1). N Engl J Med 1984; 311:235.