Medicine:Hyperimmunoglobulin E syndrome

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Hyper-IgE syndrome
Other namesHIES

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.

Presentation

It is characterized by recurrent "cold" staphylococcal infections (due to impaired recruitment of neutrophils),[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 (> 2000 IU/mL or 4800 mcg/L)[3] concentrations of the serum antibody IgE. Inheritance can be autosomal dominant or autosomal recessive.[4] 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.[5]

Pathophysiology

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] This altered pathway directly reduces the modulation capacity of interleukins 6 and 10 which, respectively, inhibit the genesis of Th17 cells that, in tandem with CD4 cells, protect against bacterial and fungal infections, and foster the inappropriate immune responses exhibited by those with Job Syndrome.[11]

Autosomal recessive:

  • DOCK8 - DOCK8 Immunodeficiency Syndrome (DIDS) presents primarily with immune effects including HEIS.[12] Eczema is prominent, food[13] and environmental allergies are common,[7] and asthma and anaphylaxis has been variably reported.[7]
  • PGM3, a Congenital Disorder of Glycosylation, may present as HIES with neurocognitive impairment and hypomyelination. See PGM3 deficiency.[14]
  • SPINK5 may present as HIES with skin and hair effects such as trichorrhexis invaginata (bamboo hair). See Netherton Syndrome (NTS).
  • TYK2 may present as HIES,[15] although more often only with immunodeficiency.[16]

Diagnosis

Elevated IgE is the hallmark of HIES. An IgE level greater than 2,000 IU/mL is often considered diagnostic.[17] 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.[18] 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.[19]

Types

HIES often appears early in life with recurrent staphylococcal and candidal infections, pneumonias, and eczematoid skin.[20]

  • 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.[18]
  • Autosomal recessive[5]

Treatment

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.[21]

History

HIES was first described by Davis et al. in 1966 in two girls with red hair, chronic dermatitis, and recurrent staphylococcal abscesses and pneumonias.[22] 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.[23]

See also

  • Isolated primary immunoglobulin M deficiency
  • List of cutaneous conditions
  • List of dental abnormalities associated with cutaneous conditions

References

  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. ↑ "hyperimmunoglobulinemia E syndrome" at Dorland's Medical Dictionary
  3. ↑ "Hyper-IgE Syndrome". Merck Sharp & Dohme Corp. https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/hyper-ige-syndrome?query=Hyper-IgE%20Syndrome. 
  4. ↑ Dermatologic Manifestations of Job Syndrome at eMedicine
  5. ↑ 5.0 5.1 Freeman, Alexandra F.; Holland, Steven M. (2008). "The Hyper-IgE Syndromes". Immunology and Allergy Clinics of North America (Elsevier BV) 28 (2): 277–291. doi:10.1016/j.iac.2008.01.005. ISSN 0889-8561. PMID 18424333. 
  6. ↑ "Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome". The Journal of Pediatrics 136 (2): 176–80. February 2000. doi:10.1016/S0022-3476(00)70098-9. PMID 10657822. 
  7. ↑ 7.0 7.1 7.2 "The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside". The World Allergy Organization Journal 5 (7): 79–87. July 2012. doi:10.1097/WOX.0b013e31825a73b2. PMID 23283142. 
  8. ↑ "Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes". Pediatric Research 65 (5 Pt 2): 32R–37R. May 2009. doi:10.1203/PDR.0b013e31819dc8c5. PMID 19190525. 
  9. ↑ "The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside". The World Allergy Organization Journal 5 (7): 79–87. July 2012. doi:10.1097/WOX.0b013e31825a73b2. PMID 23283142. 
  10. ↑ "STAT3 mutations in the hyper-IgE syndrome". The New England Journal of Medicine 357 (16): 1608–19. October 2007. doi:10.1056/NEJMoa073687. PMID 17881745. 
  11. ↑ Hafsi, Wissem; Yarrarapu, Siva Naga S. (2021), "Job Syndrome", StatPearls (Treasure Island (FL): StatPearls Publishing), PMID 30247822, http://www.ncbi.nlm.nih.gov/books/NBK525947/, retrieved 2021-11-28 
  12. ↑ "Combined immunodeficiency associated with DOCK8 mutations". The New England Journal of Medicine 361 (21): 2046–55. November 2009. doi:10.1056/NEJMoa0905506. PMID 19776401. 
  13. ↑ "Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern". Allergy 69 (7): 943–953. 2014-05-20. doi:10.1111/all.12416. PMID 24840882. 
  14. ↑ "Hyper-IgE syndromes: reviewing PGM3 deficiency". Current Opinion in Pediatrics 26 (6): 697–703. December 2014. doi:10.1097/MOP.0000000000000158. PMID 25365149. 
  15. ↑ "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity 25 (5): 745–55. November 2006. doi:10.1016/j.immuni.2006.09.009. PMID 17088085. 
  16. ↑ "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome". The Journal of Experimental Medicine 212 (10): 1641–62. September 2015. doi:10.1084/jem.20140280. PMID 26304966. 
  17. ↑ Ochs, HD; Notarangelo, LD (2010). Williams Hematology: Chapter 82. Immunodeficiency Diseases (8th ed.). New York: McGraw-Hill Medical. ISBN 9780071621519. http://www.accessmedicine.com/content.aspx?aID=6244976. 
  18. ↑ 18.0 18.1 "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder". The New England Journal of Medicine 340 (9): 692–702. March 1999. doi:10.1056/NEJM199903043400904. PMID 10053178. 
  19. ↑ Yaakoubi, Roukaya; Mekki, Najla; Ben-Mustapha, Imen; Ben-Khemis, Leila; Bouaziz, Asma; Ben Fraj, Ilhem; Ammar, Jamel; Hamzaoui, Agnès et al. (January 10, 2023). "Diagnostic challenge in a series of eleven patients with hyper IgE syndromes". Frontiers in Immunology (Frontiers Media SA) 13. doi:10.3389/fimmu.2022.1057679. ISSN 1664-3224. PMID 36703986. 
  20. ↑ "Hyper IgE syndrome". August 9, 2023. https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/hyper-ige-syndrome#:~:text=Hyper%20IgE%20Syndrome%20(HIES)%20is,high%20serum%20levels%20of%20IgE. 
  21. ↑ "High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome". The Journal of Allergy and Clinical Immunology 95 (3): 771–4. March 1995. doi:10.1016/S0091-6749(95)70185-0. PMID 7897163. 
  22. ↑ "Job's Syndrome. Recurrent, "cold", staphylococcal abscesses". Lancet 1 (7445): 1013–5. May 1966. doi:10.1016/S0140-6736(66)90119-X. PMID 4161105. 
  23. ↑ "Extreme hyperimmunoglobulinemia E and undue susceptibility to infection". Pediatrics 49 (1): 59–70. January 1972. doi:10.1542/peds.49.1.59. PMID 5059313. 

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