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Autosomal dominant hyperimmunoglobulin E syndrome

Timothy R LaPine, MD
Attila Kumánovics, MD
Harry R Hill, MD
Section Editor
Jordan S Orange, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS


A syndrome of recurrent staphylococcal abscesses, sinopulmonary infections, and severe eczema was described in 1966 in two red-haired girls [1]. The condition was initially called "Job syndrome," based upon a description of the biblical character Job: "so went Satan forth from the presence of the Lord and smote Job with sore boils from the sole of his foot unto his crown" (Job, II, 7). The cutaneous abscesses in patients with this disorder appeared "cold" (ie, lacking the typical signs of inflammation).

This disorder was termed hyperimmunoglobulin E recurrent infection syndrome (HIES) when an associated increase in serum levels of immunoglobulin E (IgE) was described [2,3]. Subsequent work revealed a broader array of clinical features and defined some of the functional defects in immune regulation in patients with classic autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES)/Job syndrome. Autosomal recessive disorders with a similar presentation were also identified.

This topic reviews the epidemiology, pathogenesis, diagnosis, and management of AD-HIES. Related disorders, such as dedicator of cytokinesis 8 (DOCK8) deficiency (while mentioned here as an autosomal recessive cause of HIES), are discussed in detail separately. (See "Combined immunodeficiencies", section on 'Dedicator of cytokinesis 8 deficiency'.)

Patients with this syndrome have characteristic facial features and skeletal findings, and have recurrent infections (principally bacterial and Candida infections) and dermatitis [3-5].

In addition to elevated levels of serum IgE, there are abnormalities in the inflammatory process and associated immune regulatory defects.


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Literature review current through: Feb 2017. | This topic last updated: Wed Feb 22 00:00:00 GMT+00:00 2017.
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  1. Davis SD, Schaller J, Wedgwood RJ. Job's Syndrome. Recurrent, "cold", staphylococcal abscesses. Lancet 1966; 1:1013.
  2. Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 1972; 49:59.
  3. Hill HR, Quie PG. Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections. Lancet 1974; 1:183.
  4. Hill HR, Ochs HD, Quie PG, et al. Defect in neutrophil granulocyte chemotaxis in Job's syndrome of recurrent "cold" staphylococcal abscesses. Lancet 1974; 2:617.
  5. Borges WG, Hensley T, Carey JC, et al. The face of Job. J Pediatr 1998; 133:303.
  6. Woellner C, Gertz EM, Schäffer AA, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol 2010; 125:424.
  7. Mogensen TH. STAT3 and the Hyper-IgE syndrome: Clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. JAKSTAT 2013; 2:e23435.
  8. National Institutes of Health. Genetic and Rare Diseases Information Center (GARD). Hyper IgE syndrome. http://rarediseases.info.nih.gov/gard/10956/hyperimmunoglobulin-e-syndrome/Resources/1 (Accessed on May 27, 2014).
  9. Chandesris MO, Melki I, Natividad A, et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore) 2012; 91:e1.
  10. Minegishi Y, Saito M, Tsuchiya S, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007; 448:1058.
  11. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007; 357:1608.
  12. Gene Reviews. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=higes (Accessed on June 02, 2010).
  13. Kumánovics A, Wittwer CT, Pryor RJ, et al. Rapid molecular analysis of the STAT3 gene in Job syndrome of hyper-IgE and recurrent infectious diseases. J Mol Diagn 2010; 12:213.
  14. Heimall J, Davis J, Shaw PA, et al. Paucity of genotype-phenotype correlations in STAT3 mutation positive Hyper IgE Syndrome (HIES). Clin Immunol 2011; 139:75.
  15. Renner ED, Rylaarsdam S, Anover-Sombke S, et al. Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. J Allergy Clin Immunol 2008; 122:181.
  16. Hsu AP, Sowerwine KJ, Lawrence MG, et al. Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism. J Allergy Clin Immunol 2013; 131:1586.
  17. Spielberger BD, Woellner C, Dueckers G, et al. Challenges of genetic counseling in patients with autosomal dominant diseases, such as the hyper-IgE syndrome (STAT3-HIES). J Allergy Clin Immunol 2012; 130:1426.
  18. Alcántara-Montiel JC, Staines-Boone T, López-Herrera G, et al. Somatic mosaicism in B cells of a patient with autosomal dominant hyper IgE syndrome. Eur J Immunol 2016; 46:2438.
  19. Minegishi Y, Saito M, Morio T, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 2006; 25:745.
  20. Kilic SS, Hacimustafaoglu M, Boisson-Dupuis S, et al. A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J Pediatr 2012; 160:1055.
  21. Al Khatib S, Keles S, Garcia-Lloret M, et al. Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome. J Allergy Clin Immunol 2009; 124:342.
  22. Alsum Z, Hawwari A, Alsmadi O, et al. Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients. J Clin Immunol 2013; 33:55.
  23. Minegishi Y, Karasuyama H. Defects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency. Int Immunol 2009; 21:105.
  24. Heimall J, Freeman A, Holland SM. Pathogenesis of hyper IgE syndrome. Clin Rev Allergy Immunol 2010; 38:32.
  25. Maródi L, Cypowyj S, Tóth B, et al. Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. J Allergy Clin Immunol 2012; 130:1019.
  26. Darnell JE Jr. STATs and gene regulation. Science 1997; 277:1630.
  27. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002; 285:1.
  28. Levy DE, Lee CK. What does Stat3 do? J Clin Invest 2002; 109:1143.
  29. Paulson ML, Freeman AF, Holland SM. Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. Curr Opin Allergy Clin Immunol 2008; 8:527.
  30. van de Veerdonk FL, Marijnissen RJ, Joosten LA, et al. Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency. Clin Exp Immunol 2010; 159:57.
  31. Ochs HD, Oukka M, Torgerson TR. TH17 cells and regulatory T cells in primary immunodeficiency diseases. J Allergy Clin Immunol 2009; 123:977.
  32. Minegishi Y, Saito M, Nagasawa M, et al. Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. J Exp Med 2009; 206:1291.
  33. Van Scoy RE, Hill HR, Ritts RE, Quie PG. Familial neutrophil chemotaxis defect, recurrent bacterial infections, mucocutaneous candidiasis, and hyperimmunoglobulinemia E. Ann Intern Med 1975; 82:766.
  34. Hill DJ, Thompson PJ, Stewart GA, et al. The Melbourne house dust mite study: eliminating house dust mites in the domestic environment. J Allergy Clin Immunol 1997; 99:323.
  35. Donabedian H, Gallin JI. The hyperimmunoglobulin E recurrent-infection (Job's) syndrome. A review of the NIH experience and the literature. Medicine (Baltimore) 1983; 62:195.
  36. Hill HR, Quie PG. Defective neutrophil chemotaxis associated with hyperimmunoglobulinemia E. In: The Phagocytic cell in host resistance, Bellanti JA, Dayton DA (Eds), Raven Press, New York 1975. p.249.
  37. Del Prete G, Tiri A, Maggi E, et al. Defective in vitro production of gamma-interferon and tumor necrosis factor-alpha by circulating T cells from patients with the hyper-immunoglobulin E syndrome. J Clin Invest 1989; 84:1830.
  38. Ives ML, Ma CS, Palendira U, et al. Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function. J Allergy Clin Immunol 2013; 132:400.
  39. Buckley RH. The hyper-IgE syndrome. Clin Rev Allergy Immunol 2001; 20:139.
  40. Avery DT, Ma CS, Bryant VL, et al. STAT3 is required for IL-21-induced secretion of IgE from human naive B cells. Blood 2008; 112:1784.
  41. Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008; 452:773.
  42. Borges WG, Augustine NH, Hill HR. Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome. J Pediatr 2000; 136:176.
  43. Kane A, Lau A, Brink R, et al. B-cell-specific STAT3 deficiency: Insight into the molecular basis of autosomal-dominant hyper-IgE syndrome. J Allergy Clin Immunol 2016; 138:1455.
  44. Wolach O, Kuijpers T, Ben-Ari J, et al. Variable clinical expressivity of STAT3 mutation in hyperimmunoglobulin E syndrome: genetic and clinical studies of six patients. J Clin Immunol 2014; 34:163.
  45. Siegel AM, Stone KD, Cruse G, et al. Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation. J Allergy Clin Immunol 2013; 132:1388.
  46. Olaiwan A, Chandesris MO, Fraitag S, et al. Cutaneous findings in sporadic and familial autosomal dominant hyper-IgE syndrome: a retrospective, single-center study of 21 patients diagnosed using molecular analysis. J Am Acad Dermatol 2011; 65:1167.
  47. Eberting CL, Davis J, Puck JM, et al. Dermatitis and the newborn rash of hyper-IgE syndrome. Arch Dermatol 2004; 140:1119.
  48. Cho C, Ferdman RM, Church JA, Ong PY. Skin-deep clues to a complex disease. Ann Allergy Asthma Immunol 2010; 104:93.
  49. Shyur SD, Hill HR. Immunodeficiency in the 1990s. Pediatr Infect Dis J 1991; 10:595.
  50. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med 1999; 340:692.
  51. Grimbacher B, Holland SM, Puck JM. Hyper-IgE syndromes. Immunol Rev 2005; 203:244.
  52. Freeman AF, Kleiner DE, Nadiminti H, et al. Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol 2007; 119:1234.
  53. Freeman AF, Davis J, Anderson VL, et al. Pneumocystis jiroveci infection in patients with hyper-immunoglobulin E syndrome. Pediatrics 2006; 118:e1271.
  54. Vinh DC, Sugui JA, Hsu AP, et al. Invasive fungal disease in autosomal-dominant hyper-IgE syndrome. J Allergy Clin Immunol 2010; 125:1389.
  55. Shyur SD, Hill HR. Job's syndrome of hyperimmunoglobulin E and recurrent infections. In: Current therapy in allergy, immunology, and rheumatology, Lichtenstein LM, Fauci AS (Eds), Mosby-Year Book, Inc, Saint Louis, MO 1992. p.322.
  56. Melia E, Freeman AF, Shea YR, et al. Pulmonary nontuberculous mycobacterial infections in hyper-IgE syndrome. J Allergy Clin Immunol 2009; 124:617.
  57. Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005; 41:1217.
  58. Antachopoulos C, Walsh TJ, Roilides E. Fungal infections in primary immunodeficiencies. Eur J Pediatr 2007; 166:1099.
  59. Sowerwine KJ, Holland SM, Freeman AF. Hyper-IgE syndrome update. Ann N Y Acad Sci 2012; 1250:25.
  60. Odio CD, Milligan KL, McGowan K, et al. Endemic mycoses in patients with STAT3-mutated hyper-IgE (Job) syndrome. J Allergy Clin Immunol 2015; 136:1411.
  61. O'Connell AC, Puck JM, Grimbacher B, et al. Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 89:177.
  62. Domingo DL, Freeman AF, Davis J, et al. Novel intraoral phenotypes in hyperimmunoglobulin-E syndrome. Oral Dis 2008; 14:73.
  63. Scheuerman O, Hoffer V, Cohen AH, et al. Reduced bone density in patients with autosomal dominant hyper-IgE syndrome. J Clin Immunol 2013; 33:903.
  64. Sowerwine KJ, Shaw PA, Gu W, et al. Bone density and fractures in autosomal dominant hyper IgE syndrome. J Clin Immunol 2014; 34:260.
  65. Kirchner SG, Sivit CJ, Wright PF. Hyperimmunoglobulinemia E syndrome: association with osteoporosis and recurrent fractures. Radiology 1985; 156:362.
  66. Cohen-Solal M, Prieur AM, Prin L, et al. Cytokine-mediated bone resorption in patients with the hyperimmunoglobulin E syndrome. Clin Immunol Immunopathol 1995; 76:75.
  67. Leonard GD, Posadas E, Herrmann PC, et al. Non-Hodgkin's lymphoma in Job's syndrome: a case report and literature review. Leuk Lymphoma 2004; 45:2521.
  68. Kumánovics A, Perkins SL, Gilbert H, et al. Diffuse large B cell lymphoma in hyper-IgE syndrome due to STAT3 mutation. J Clin Immunol 2010; 30:886.
  69. Gorin LJ, Jeha SC, Sullivan MP, et al. Burkitt's lymphoma developing in a 7-year-old boy with hyper-IgE syndrome. J Allergy Clin Immunol 1989; 83:5.
  70. Belada D, Smolej L, Stepánková P, et al. Diffuse large B-cell lymphoma in a patient with hyper-IgE syndrome: Successful treatment with risk-adapted rituximab-based immunochemotherapy. Leuk Res 2010; 34:e232.
  71. Clark TJ, Herod JJ, Kehoe S, Luesley DM. The development of invasive vulvar cancer in a patient with Job's syndrome, a rare immunodeficient condition. Br J Obstet Gynaecol 1998; 105:468.
  72. Oztop I, Demirkan B, Tarhan O, et al. The development of pulmonary adenocarcinoma in a patient with Job's syndrome, a rare immunodeficiency condition. Tumori 2004; 90:132.
  73. Freeman AF, Collura-Burke CJ, Patronas NJ, et al. Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics 2007; 119:e1121.
  74. Martin S, Wolters P, Billings N, et al. Neurobehavioral profiles in individuals with hyperimmunoglobulin E Syndrome (HIES) and brain white matter hyperintensities. J Clin Immunol 2013; 33:1175.
  75. Yavuz H, Chee R. A review on the vascular features of the hyperimmunoglobulin E syndrome. Clin Exp Immunol 2010; 159:238.
  76. Gharib AM, Pettigrew RI, Elagha A, et al. Coronary abnormalities in hyper-IgE recurrent infection syndrome: depiction at coronary MDCT angiography. AJR Am J Roentgenol 2009; 193:W478.
  77. de Saint-Basile G. Other well-defined immunodeficiency syndromes (The Hyper-IgE Syndrome). In: Immunologic disorders in infants and children, 5th, Stiehm ER, Ochs HD, Winkelstein JA (Eds), Elsevier Saunders, Philadelphia 2004. p.544.
  78. Joshi AY, Iyer VN, Boyce TG, et al. Elevated serum immunoglobulin E (IgE): when to suspect hyper-IgE syndrome-A 10-year pediatric tertiary care center experience. Allergy Asthma Proc 2009; 30:23.
  79. Schimke LF, Sawalle-Belohradsky J, Roesler J, et al. Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis. J Allergy Clin Immunol 2010; 126:611.
  80. Aydin SE, Kilic SS, Aytekin C, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients. J Clin Immunol 2015; 35:189.
  81. Boos AC, Hagl B, Schlesinger A, et al. Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern. Allergy 2014; 69:943.
  82. Sheerin KA, Buckley RH. Antibody responses to protein, polysaccharide, and phi X174 antigens in the hyperimmunoglobulinemia E (hyper-IgE) syndrome. J Allergy Clin Immunol 1991; 87:803.
  83. Leung DY, Ambrosino DM, Arbeit RD, et al. Impaired antibody responses in the hyperimmunoglobulin E syndrome. J Allergy Clin Immunol 1988; 81:1082.
  84. Pien GC, Orange JS. Evaluation and clinical interpretation of hypergammaglobulinemia E: differentiating atopy from immunodeficiency. Ann Allergy Asthma Immunol 2008; 100:392.
  85. Ozcan E, Notarangelo LD, Geha RS. Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol 2008; 122:1054.
  86. Sassi A, Lazaroski S, Wu G, et al. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J Allergy Clin Immunol 2014; 133:1410.
  87. Zhang Y, Yu X, Ichikawa M, et al. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J Allergy Clin Immunol 2014; 133:1400.
  88. Buckley RH. Other well-defined immunodeficiency syndromes (The Hyper-IgE Syndrome). In: Immunologic disorders in infants and children, 5th ed, Stiehm ER, Ochs HD, Winkelstein JA (Eds), Elsevier Saunders, Philadelphia 2004. p.550.
  89. Stray-Pedersen A, Backe PH, Sorte HS, et al. PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. Am J Hum Genet 2014; 95:96.
  90. Quie PG, Belani KR. Hyperimmunoglobulin E syndrome. In: Current therapy in allergy, immunology, and rheumatology, Lichtenstein LM, Fauci AS (Eds), Mosby-Year Book, Inc, Saint Louis, MO 1988. p.313.
  91. Erlewyn-Lajeunesse MD. Hyperimmunoglobulin-E syndrome with recurrent infection: a review of current opinion and treatment. Pediatr Allergy Immunol 2000; 11:133.
  92. Freeman AF, Renner ED, Henderson C, et al. Lung parenchyma surgery in autosomal dominant hyper-IgE syndrome. J Clin Immunol 2013; 33:896.
  93. Petrak BA, Augustine NH, Hill HR. Recombinant human interferon gamma treatment of patients with Job's syndrome of hyperimmunoglobulin E and recurrent infections. Clin Res 1994; 42:1A.
  94. King CL, Gallin JI, Malech HL, et al. Regulation of immunoglobulin production in hyperimmunoglobulin E recurrent-infection syndrome by interferon gamma. Proc Natl Acad Sci U S A 1989; 86:10085.
  95. Kimata H. High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol 1995; 95:771.
  96. Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 2008; 100:153.
  97. Wakim M, Alazard M, Yajima A, et al. High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol 1998; 81:153.
  98. Chularojanamontri L, Wimoolchart S, Tuchinda P, et al. Role of omalizumab in a patient with hyper-IgE syndrome and review dermatologic manifestations. Asian Pac J Allergy Immunol 2009; 27:233.
  99. Staines Boone AT, Alcántara-Montiel JC, Sánchez-Sánchez LM, et al. Zoledronate as effective treatment for minimal trauma fractures in a child with STAT3 deficiency and osteonecrosis of the hip. Pediatr Blood Cancer 2016; 63:2054.
  100. Nester TA, Wagnon AH, Reilly WF, et al. Effects of allogeneic peripheral stem cell transplantation in a patient with job syndrome of hyperimmunoglobulinemia E and recurrent infections. Am J Med 1998; 105:162.
  101. Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant 2000; 25:1303.
  102. Goussetis E, Peristeri I, Kitra V, et al. Successful long-term immunologic reconstitution by allogeneic hematopoietic stem cell transplantation cures patients with autosomal dominant hyper-IgE syndrome. J Allergy Clin Immunol 2010; 126:392.
  103. Yanagimachi M, Ohya T, Yokosuka T, et al. The Potential and Limits of Hematopoietic Stem Cell Transplantation for the Treatment of Autosomal Dominant Hyper-IgE Syndrome. J Clin Immunol 2016; 36:511.
  104. Patel NC, Gallagher JL, Torgerson TR, Gilman AL. Successful haploidentical donor hematopoietic stem cell transplant and restoration of STAT3 function in an adolescent with autosomal dominant hyper-IgE syndrome. J Clin Immunol 2015; 35:479.