Hyperimmunoglobulin E syndrome

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Hyper-IgE syndrome
Other names: HIES
Hyperimmunoglobulin E syndrome Coarse facies, broad nose, angular cheilitis

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.


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.[2]
  • Autosomal recessive

Signs and symptoms

Image shows retained primary dentition of the left maxillary first molar

It is characterized by recurrent "cold" staphylococcal infections (due to impaired recruitment of neutrophils),[3] 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 (> 2000 IU/mL or 4800 mcg/L)[4] concentrations of the serum antibody IgE.

Inheritance can be autosomal dominant or autosomal recessive.[5]

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.[6]

Both autosomal dominant and recessive inheritance have been described:[7][8]

Autosomal dominant:

  • STAT3 may present as HIES with characteristic facial, dental, and skeletal abnormalities[9] 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.[10]

Autosomal recessive:


Elevated IgE is the hallmark of HIES. An IgE level greater than 2,000 IU/mL is often considered diagnostic.[16] 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.[2] 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.[citation needed]


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.[17]


HIES was first described by Davis et al. in 1966 in two girls with red hair, chronic dermatitis, and recurrent staphylococcal abscesses and pneumonias.[18] 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.[19]

See also


  1. 1.0 1.1 1.2 Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
  2. 2.0 2.1 Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et al. (March 1999). "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder". The New England Journal of Medicine. 340 (9): 692–702. doi:10.1056/NEJM199903043400904. PMID 10053178.
  3. "hyperimmunoglobulinemia E syndrome" at Dorland's Medical Dictionary
  4. "Hyper-IgE Syndrome". Merck Manual. Merck Sharp & Dohme Corp. Archived from the original on 3 August 2021. Retrieved 3 August 2021.
  5. Dermatologic Manifestations of Job Syndrome at eMedicine
  6. Borges WG, Augustine NH, Hill HR (February 2000). "Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome". The Journal of Pediatrics. 136 (2): 176–80. doi:10.1016/S0022-3476(00)70098-9. PMID 10657822.
  7. 7.0 7.1 7.2 Rael EL, Marshall RT, McClain JJ (July 2012). "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. PMC 3651150. PMID 23283142.
  8. Freeman AF, Holland SM (May 2009). "Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes". Pediatric Research. 65 (5 Pt 2): 32R–37R. doi:10.1203/PDR.0b013e31819dc8c5. PMC 2919366. PMID 19190525.
  9. Rael EL, Marshall RT, McClain JJ (July 2012). "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. PMC 3651150. PMID 23283142.
  10. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. (October 2007). "STAT3 mutations in the hyper-IgE syndrome". The New England Journal of Medicine. 357 (16): 1608–19. doi:10.1056/NEJMoa073687. PMID 17881745.
  11. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. (November 2009). "Combined immunodeficiency associated with DOCK8 mutations". The New England Journal of Medicine. 361 (21): 2046–55. doi:10.1056/NEJMoa0905506. PMC 2965730. PMID 19776401.
  12. Boos AC, Hagl B, Schlesinger A, Halm BE, Ballenberger N, Pinarci M, et al. (2014-05-20). "Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern". Allergy. 69 (7): 943–953. doi:10.1111/all.12416. PMID 24840882.
  13. Yang L, Fliegauf M, Grimbacher B (December 2014). "Hyper-IgE syndromes: reviewing PGM3 deficiency". Current Opinion in Pediatrics. 26 (6): 697–703. doi:10.1097/MOP.0000000000000158. PMID 25365149. S2CID 24566050.
  14. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. (November 2006). "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity. 25 (5): 745–55. doi:10.1016/j.immuni.2006.09.009. PMID 17088085.
  15. Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramírez-Alejo N, Kilic SS, et al. (September 2015). "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome". The Journal of Experimental Medicine. 212 (10): 1641–62. doi:10.1084/jem.20140280. PMC 4577846. PMID 26304966.
  16. Ochs, HD; Notarangelo, LD (2010). Williams Hematology: Chapter 82. Immunodeficiency Diseases (8th ed.). New York: McGraw-Hill Medical. ISBN 9780071621519. Archived from the original on 2013-06-02. Retrieved 2021-08-03.
  17. Kimata H (March 1995). "High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome". The Journal of Allergy and Clinical Immunology. 95 (3): 771–4. doi:10.1016/S0091-6749(95)70185-0. PMID 7897163.
  18. Davis SD, Schaller J, Wedgwood RJ (May 1966). "Job's Syndrome. Recurrent, "cold", staphylococcal abscesses". Lancet. 1 (7445): 1013–5. doi:10.1016/S0140-6736(66)90119-X. PMID 4161105.
  19. Buckley RH, Wray BB, Belmaker EZ (January 1972). "Extreme hyperimmunoglobulinemia E and undue susceptibility to infection". Pediatrics. 49 (1): 59–70. PMID 5059313.

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