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

Hyperimmunoglobulin M syndromes

Luigi D Notarangelo, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS


The hyperimmunoglobulin M (hyper-IgM or HIGM) syndromes include a heterogeneous group of conditions characterized by defective class-switch recombination (CSR), resulting in normal or increased levels of serum IgM associated with deficiency of IgG, IgA, and IgE and poor antibody function [1]. Hyper-IgM syndrome includes several genetically determined diseases [2,3], but may also be secondary to congenital rubella syndrome [4], use of phenytoin, T cell leukemia, or lymphomas [1]. This topic review discusses in detail only genetically determined forms of hyper-IgM syndrome. (See "Congenital rubella syndrome: Clinical features and diagnosis".)


All forms of hyper-IgM syndrome are rare. The estimated frequency of CD40 ligand (CD40L) deficiency is 2:1,000,000 males [5]. Although no data are available on the frequency of activation-induced cytidine deaminase (AID) deficiency, this disorder is estimated to affect fewer than 1:1,000,000 individuals. In contrast, there are only a few reported cases of CD40 [6-9] and uracil N-glycosylase (UNG) [10] deficiencies. There is parental consanguinity in several families with autosomal recessive hyper-IgM syndrome.


Maturation of antibody responses is marked by a series of events that include (see "Immunoglobulin genetics"):

Class-switch recombination (CSR, also called class-switching), whereby the immunoglobulin mu heavy chain is replaced by other heavy chain isotypes with distinct biologic properties, resulting in production of immunoglobulin isotypes other than IgM.

Somatic hypermutation (SHM), by which somatic mutations are introduced in the variable region of actively transcribed immunoglobulin genes, thereby allowing production of high-affinity antibodies.


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: Sep 2016. | This topic last updated: Jul 15, 2015.
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.
  1. Notarangelo LD, Duse M, Ugazio AG. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev 1992; 3:101.
  2. Kracker S, Gardes P, Mazerolles F, Durandy A. Immunoglobulin class switch recombination deficiencies. Clin Immunol 2010; 135:193.
  3. Davies EG, Thrasher AJ. Update on the hyper immunoglobulin M syndromes. Br J Haematol 2010; 149:167.
  4. Ameratunga R, Woon ST, Koopmans W, French J. Cellular and molecular characterisation of the hyper immunoglobulin M syndrome associated with congenital rubella infection. J Clin Immunol 2009; 29:99.
  5. Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003; 82:373.
  6. Ferrari S, Giliani S, Insalaco A, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A 2001; 98:12614.
  7. Kutukculer N, Moratto D, Aydinok Y, et al. Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J Pediatr 2003; 142:194.
  8. Mazzolari E, Lanzi G, Forino C, et al. First report of successful stem cell transplantation in a child with CD40 deficiency. Bone Marrow Transplant 2007; 40:279.
  9. Lanzi G, Ferrari S, Vihinen M, et al. Different molecular behavior of CD40 mutants causing hyper-IgM syndrome. Blood 2010; 116:5867.
  10. Imai K, Slupphaug G, Lee WI, et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 2003; 4:1023.
  11. Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol 2008; 26:261.
  12. Elgueta R, Benson MJ, de Vries VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 2009; 229:152.
  13. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 2000; 102:565.
  14. Péron S, Metin A, Gardès P, et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 2008; 205:2465.
  15. Maul RW, Gearhart PJ. AID and somatic hypermutation. Adv Immunol 2010; 105:159.
  16. Korthäuer U, Graf D, Mages HW, et al. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 1993; 361:539.
  17. Allen RC, Armitage RJ, Conley ME, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 1993; 259:990.
  18. Aruffo A, Farrington M, Hollenbaugh D, et al. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 1993; 72:291.
  19. DiSanto JP, Bonnefoy JY, Gauchat JF, et al. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature 1993; 361:541.
  20. Fuleihan R, Ramesh N, Loh R, et al. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A 1993; 90:2170.
  21. Meyers G, Ng YS, Bannock JM, et al. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc Natl Acad Sci U S A 2011; 108:11554.
  22. Jain A, Ma CA, Liu S, et al. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2001; 2:223.
  23. Hanson EP, Monaco-Shawver L, Solt LA, et al. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol 2008; 122:1169.
  24. Döffinger R, Smahi A, Bessia C, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 2001; 27:277.
  25. Pan-Hammarström Q, Lähdesmäki A, Zhao Y, et al. Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation. J Exp Med 2006; 203:99.
  26. de Saint Basile G, Tabone MD, Durandy A, et al. CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization. Eur J Immunol 1999; 29:367.
  27. Imai K, Shimadzu M, Kubota T, et al. Female hyper IgM syndrome type 1 with a chromosomal translocation disrupting CD40LG. Biochim Biophys Acta 2006; 1762:335.
  28. Kasahara Y, Kaneko H, Fukao T, et al. Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase. J Allergy Clin Immunol 2003; 112:755.
  29. Imai K, Zhu Y, Revy P, et al. Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2. Clin Immunol 2005; 115:277.
  30. Imai K, Catalan N, Plebani A, et al. Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination. J Clin Invest 2003; 112:136.
  31. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997; 131:47.
  32. Aghamohammadi A, Parvaneh N, Rezaei N, et al. Clinical and laboratory findings in hyper-IgM syndrome with novel CD40L and AICDA mutations. J Clin Immunol 2009; 29:769.
  33. Simon G, Simon G, Erdös M, Maródi L. Invasive Cryptococcus laurentii disease in a nine-year-old boy with X-linked hyper-immunoglobulin M syndrome. Pediatr Infect Dis J 2005; 24:935.
  34. Yong PF, Post FA, Gilmour KC, et al. Cerebral toxoplasmosis in a middle-aged man as first presentation of primary immunodeficiency due to a hypomorphic mutation in the CD40 ligand gene. J Clin Pathol 2008; 61:1220.
  35. Suzuki H, Takahashi Y, Miyajima H. Progressive multifocal leukoencephalopathy complicating X-linked hyper-IgM syndrome in an adult. Intern Med 2006; 45:1187.
  36. Aschermann Z, Gomori E, Kovacs GG, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol 2007; 64:273.
  37. Hayward AR, Levy J, Facchetti F, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol 1997; 158:977.
  38. Erdos M, Garami M, Rákóczi E, et al. Neuroendocrine carcinoma associated with X-linked hyper-immunoglobulin M syndrome: report of four cases and review of the literature. Clin Immunol 2008; 129:455.
  39. Filipovich AH, Mathur A, Kamat D, et al. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency 1994; 5:91.
  40. Lopez-Granados E, Temmerman ST, Wu L, et al. Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc Natl Acad Sci U S A 2007; 104:5056.
  41. Minegishi Y, Lavoie A, Cunningham-Rundles C, et al. Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. Clin Immunol 2000; 97:203.
  42. Quartier P, Bustamante J, Sanal O, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency. Clin Immunol 2004; 110:22.
  43. Agematsu K, Nagumo H, Shinozaki K, et al. Absence of IgD-CD27(+) memory B cell population in X-linked hyper-IgM syndrome. J Clin Invest 1998; 102:853.
  44. Puga I, Cols M, Cerutti A. Innate signals in mucosal immunoglobulin class switching. J Allergy Clin Immunol 2010; 126:889.
  45. Lee WI, Torgerson TR, Schumacher MJ, et al. Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood 2005; 105:1881.
  46. Jain A, Kovacs JA, Nelson DL, et al. Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand. Blood 2011; 118:3811.
  47. Jain A, Atkinson TP, Lipsky PE, et al. Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome. J Clin Invest 1999; 103:1151.
  48. DeKruyff RH, Gieni RS, Umetsu DT. Antigen-driven but not lipopolysaccharide-driven IL-12 production in macrophages requires triggering of CD40. J Immunol 1997; 158:359.
  49. Facchetti F, Appiani C, Salvi L, et al. Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells. J Immunol 1995; 154:6624.
  50. Cabral-Marques O, Arslanian C, Ramos RN, et al. Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis. J Allergy Clin Immunol 2012; 129:778.
  51. Fontana S, Moratto D, Mangal S, et al. Functional defects of dendritic cells in patients with CD40 deficiency. Blood 2003; 102:4099.
  52. Brugnoni D, Airò P, Graf D, et al. Ontogeny of CD40L [corrected] expression by activated peripheral blood lymphocytes in humans. Immunol Lett 1996; 49:27.
  53. Gilmour KC, Walshe D, Heath S, et al. Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM. Mol Pathol 2003; 56:256.
  54. Bonilla FA, Geha RS. CD154 deficiency and related syndromes. Immunol Allergy Clin North Am 2001; 21:65.
  55. Seyama K, Nonoyama S, Gangsaas I, et al. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood 1998; 92:2421.
  56. Notarangelo LD, Peitsch MC, Abrahamsen TG, et al. CD40lbase: a database of CD40L gene mutations causing X-linked hyper-IgM syndrome. Immunol Today 1996; 17:511.
  57. Chou J, Hanna-Wakim R, Tirosh I, et al. A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome. J Allergy Clin Immunol 2012; 130:1414.
  58. Deau MC, Heurtier L, Frange P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest 2014; 124:3923.
  59. Lucas CL, Zhang Y, Venida A, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med 2014; 211:2537.
  60. Farrington M, Grosmaire LS, Nonoyama S, et al. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci U S A 1994; 91:1099.
  61. Brugnoni D, Airò P, Lebovitz M, et al. CD4+ cells from patients with Common Variable Immunodeficiency have a reduced ability of CD40 ligand membrane expression after in vitro stimulation. Pediatr Allergy Immunol 1996; 7:176.
  62. O'Gorman MR, Zaas D, Paniagua M, et al. Development of a rapid whole blood flow cytometry procedure for the diagnosis of X-linked hyper-IgM syndrome patients and carriers. Clin Immunol Immunopathol 1997; 85:172.
  63. Wang WC, Cordoba J, Infante AJ, Conley ME. Successful treatment of neutropenia in the hyper-immunoglobulin M syndrome with granulocyte colony-stimulating factor. Am J Pediatr Hematol Oncol 1994; 16:160.
  64. Gennery AR, Khawaja K, Veys P, et al. Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002. Blood 2004; 103:1152.
  65. Gennery AR, Slatter MA, Grandin L, et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol 2010; 126:602.
  66. Tomizawa D, Imai K, Ito S, et al. Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: a single center experience. Am J Hematol 2004; 76:33.
  67. McLauchlin J, Amar CF, Pedraza-Díaz S, et al. Polymerase chain reaction-based diagnosis of infection with Cryptosporidium in children with primary immunodeficiencies. Pediatr Infect Dis J 2003; 22:329.
  68. Hadzić N, Pagliuca A, Rela M, et al. Correction of the hyper-IgM syndrome after liver and bone marrow transplantation. N Engl J Med 2000; 342:320.
  69. Notarangelo L, Harvard Medical School, 2012, personal communication.
  70. Karaca NE, Durandy A, Gulez N, et al. Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature. Eur J Pediatr 2011; 170:1039.