Hyperimmunoglobulin E syndrome

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Hyper-IgE syndrome
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Hyperimmunoglobulinemia E syndrome[1] (HIES), of which the autosomal dominant form is called Job's syndrome[1] or Buckley syndrome,[1] is a heterogeneous group of immune disorders. Job's is also very rare at about 300 cases currently in the literature.


It is characterized by recurrent "cold" staphylococcal infections,[2] unusual eczema-like skin rashes, severe lung infections that result in pneumatoceles (balloon-like lesions that may be filled with air or pus or scar tissue) and very high concentrations of the serum antibody IgE. Inheritance can be autosomal dominant or autosomal recessive.[3] Many patients with autosomal dominant STAT3 hyper-IgE syndrome have characteristic facial and dental abnormalities, fail to lose their primary teeth, and have two sets of teeth simultaneously.


Abnormal neutrophil chemotaxis due to decreased production of interferon gamma by T lymphocytes is thought to cause the disease.[4]

Both autosomal dominant and recessive inheritance have been described:[5][6]

Autosomal dominant:

  • STAT3 may present as HIES with characteristic facial, dental, and skeletal abnormalities[7] that has been called Job's Syndrome. A common mnemonic used to remember the symptoms is FATED: coarse or leonine facies, cold staph abscesses, retained primary teeth, increased IgE, and dermatologic problems [eczema]. The disease was linked to mutations in the STAT3 gene after cytokine profiles indicated alterations in the STAT3 pathway.[8]

Autosomal recessive:


Elevated IgE is the hallmark of HIES. An IgE level greater than 2,000 IU/mL is often considered diagnostic.[14] However, patients younger than 6 months of age may have very low to non-detectable IgE levels. Eosinophilia is also a common finding with greater than 90% of patients having eosinophil elevations greater than two standard deviations above the normal mean.[15] Genetic testing is available for STAT3 (Job's Syndrome), DOCK8 (DOCK8 Immunodeficiency or DIDS), PGM3 (PGM3 deficiency), SPINK5 (Netherton Syndrome - NTS), and TYK2 genetic defects.


HIES often appears early in life with recurrent staphylococcal and candidal infections, pneumonias, and eczematoid skin.

  • Autosomal dominant Hyper-IgE Syndrome caused by STAT3 defects, called Job Syndrome, have characteristic facial, dental, and skeletal abnormalities. Patients with STAT3 HIES may have either delay of or failure in shedding of primary teeth. The characteristic facial features are usually set by age 16. These include facial asymmetry, a prominent forehead, deep-set eyes, a broad nasal bridge, a wide, fleshy nasal tip, and mild prognathism. Additionally, facial skin is rough with prominent pores. Finally, some patients with STAT3 HIES have scoliosis, as well as bones that fracture easily.[15]
  • Autosomal recessive


Most patients with hyper IgE syndrome are treated with long-term antibiotic therapy to prevent staphylococcal infections. Good skin care is also important in patients with hyper IgE syndrome. High-dose intravenous gamma-globulin has also been suggested for the treatment of severe eczema in patients with HIES and atopic dermatitis.[16]


HIES was first described by Davis et al. in 1966 in two girls with red hair, chronic dermatitis, and recurrent staphylococcal abscesses and pneumonias.[17] They named the disease after the biblical figure Job, whose body was covered with boils by Satan. In 1972, Buckley et al. described two boys with similar symptoms as well as coarse facies, eosinophilia, and elevated serum IgE levels. These two syndromes are thought to be the same and are under the broad category of HIES.[18]

See also[edit]


  1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
  2. ^ "hyperimmunoglobulinemia E syndrome" at Dorland's Medical Dictionary
  3. ^ Dermatologic Manifestations of Job Syndrome at eMedicine
  4. ^ Borges W, Augustine N, Hill H (2000). "Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome". J Pediatr. 136 (2): 176–80. doi:10.1016/S0022-3476(00)70098-9. PMID 10657822.
  5. ^ a b c Rael, Efren L; Marshall, Robert T; McClain, Jonathan J (2012-07-15). "The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside". The World Allergy Organization Journal. 5 (7): 79–87. doi:10.1097/WOX.0b013e31825a73b2. ISSN 1939-4551. PMC 3651150. PMID 23283142.
  6. ^ Freeman, Alexandra F.; Holland, Steven M. (2009-05-01). "Clinical Manifestations, Etiology, and Pathogenesis of the Hyper IgE Syndromes". Pediatric Research. 65 (5 Pt 2): 32R–37R. doi:10.1203/PDR.0b013e31819dc8c5. ISSN 0031-3998. PMC 2919366. PMID 19190525.
  7. ^ Rael, Efren L.; Marshall, Robert T.; McClain, Jonathan J. (2012-07-01). "The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside". The World Allergy Organization Journal. 5 (7): 79–87. doi:10.1097/WOX.0b013e31825a73b2. ISSN 1939-4551. PMC 3651150. PMID 23283142.
  8. ^ Holland, Steven M.; DeLeo, Frank R.; Elloumi, Houda Z.; Hsu, Amy P.; Uzel, Gulbu; Brodsky, Nina; Freeman, Alexandra F.; Demidowich, Andrew; Davis, Joie; Turner, Maria L.; Anderson, Victoria L.; Darnell, Dirk N.; Welch, Pamela A.; Kuhns, Douglas B.; Frucht, David M.; Malech, Harry L.; Gallin, John I.; Kobayashi, Scott D.; Whitney, Adeline R.; Voyich, Jovanka M.; Musser, James M.; Woellner, Cristina; Schäffer, Alejandro A.; Puck, Jennifer M.; Grimbacher, Bodo (2007). "STAT3 Mutations in the Hyper-IgE Syndrome". The New England Journal of Medicine. 357 (16): 1608–19. doi:10.1056/NEJMoa073687. PMID 17881745.
  9. ^ Zhang Q; Davis JC; Lamborn IT; et al. (November 2009). "Combined immunodeficiency associated with DOCK8 mutations". N. Engl. J. Med. 361 (21): 2046–55. doi:10.1056/NEJMoa0905506. PMC 2965730. PMID 19776401.
  10. ^ Boos, A. C.; Hagl, B.; Schlesinger, A.; Halm, B. E.; Ballenberger, N.; Pinarci, M.; Heinz, V.; Kreilinger, D.; Spielberger, B. D. (2014-05-20). "Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern". Allergy. 69: 943–953. doi:10.1111/all.12416. ISSN 1398-9995. PMID 24840882.
  11. ^ Yang, Linlin; Fliegauf, Manfred; Grimbacher, Bodo (2014-12-01). "Hyper-IgE syndromes: reviewing PGM3 deficiency". Current Opinion in Pediatrics. 26 (6): 697–703. doi:10.1097/MOP.0000000000000158. ISSN 1531-698X. PMID 25365149.
  12. ^ Minegishi, Yoshiyuki; Saito, Masako; Morio, Tomohiro; Watanabe, Ken; Agematsu, Kazunaga; Tsuchiya, Shigeru; Takada, Hidetoshi; Hara, Toshiro; Kawamura, Nobuaki (2006-11-01). "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity. 25 (5): 745–755. doi:10.1016/j.immuni.2006.09.009. ISSN 1074-7613. PMID 17088085.
  13. ^ Kreins, Alexandra Y.; Ciancanelli, Michael J.; Okada, Satoshi; Kong, Xiao-Fei; Ramírez-Alejo, Noé; Kilic, Sara Sebnem; El Baghdadi, Jamila; Nonoyama, Shigeaki; Mahdaviani, Seyed Alireza (2015-09-21). "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome". The Journal of Experimental Medicine. 212 (10): 1641–1662. doi:10.1084/jem.20140280. ISSN 1540-9538. PMC 4577846. PMID 26304966.
  14. ^ Ochs, HD; Notarangelo, LD (2010). Williams Hematology: Chapter 82. Immunodeficiency Diseases (8th ed.). New York: McGraw-Hill Medical. ISBN 9780071621519.
  15. ^ a b Grimbacher B, Holland S, Gallin J, Greenberg F, Hill S, Malech H, Miller J, O'Connell A, Puck J (1999). "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder". N Engl J Med. 340 (9): 692–702. doi:10.1056/NEJM199903043400904. PMID 10053178.
  16. ^ Kimata H (1995). "High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome". J Allergy Clin Immunol. 95 (3): 771–4. doi:10.1016/S0091-6749(95)70185-0. PMID 7897163.
  17. ^ Davis S, Schaller J, Wedgwood R (1966). "Job's Syndrome. Recurrent, "cold", staphylococcal abscesses". Lancet. 1 (7445): 1013–5. doi:10.1016/S0140-6736(66)90119-X. PMID 4161105.
  18. ^ Buckley R, Wray B, Belmaker E (1972). "Extreme hyperimmunoglobulinemia E and undue susceptibility to infection". Pediatrics. 49 (1): 59–70. PMID 5059313.

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