Dermatologic Manifestations of Job Syndrome 

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Apr 12, 2011
 

Background

First described in 1966, the hyperimmunoglobulin E (hyper-IgE or HIE) syndrome is a rare immunodeficiency disorder that has an autosomal dominant inheritance pattern. HIE syndrome has variable expressivity and is associated with multiple abnormalities. The most common findings are recurrent skin abscesses (hence, the name Job syndrome), pneumonia with pneumatocele development, and high serum levels of IgE. Facial, dental, and skeletal features are also associated with this syndrome.

Although most cases are sporadic, multiplex families displaying autosomal dominant and autosomal recessive inheritance have been described.[1] Autosomal recessive patients tend to have severe molluscum contagiosum and other viral infections and may develop severe neurological complications. These patients also lack skeletal or dental involvement and do not develop lung cysts. Some authorities believe 2 separate syndromes exist, not one.

Type 1 HIE syndrome displays abnormalities in multiple systems, including the skeletal, dental, and immune systems, whereas type 2 HIE syndrome shows abnormalities confined to the immune system.[2] Hypomorphic mutations have been found in the signal transducer and activator of transcription 3 (STAT3) gene in type 1 HIE syndrome and a null mutation in the tyrosine kinase 2 (Tyk2) gene. Cytokine responses in both types of HIE syndrome revealed severe defects leading to impaired T-helper type 17 function. Another study credited deficiency of Th17 cells in HIE syndrome to mutations in STAT3 in a majority of evaluated patients.[3] However, defective Th17 responses may be seen in classic disease without STAT3 mutations, with the extent of the defective Th17 response postulated to determine the clinical phenotype.[4]

Also see the eMedicine pediatrics article Hyperimmunoglobulinemia E (Job) Syndrome.

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Pathophysiology

The pathophysiology of Job syndrome (HIE syndrome, or hyper-IgE syndrome) is not completely understood. Patients consistently have a poor, delayed hypersensitivity response to antigens. This delayed response is associated with alterations in T-lymphocyte populations and various interleukin and cytokine abnormalities.[5] One of the earliest reports on the pathophysiology of Job syndrome described a chemotactic defect in neutrophils.[6] This defect has since been attributed to defective production of interferon-gamma, a major activator of neutrophils when stimulated by interleukin (IL)–12. The poor production of interferon-gamma in response to IL-12 results in the marked elevation of IgE levels (by means of unopposed IL-4 action).[7]

Other factors in the abnormal immunologic response are described. Patients with HIE syndrome have elevated levels of granulocyte-macrophage colony-stimulating factor, which may also explain the decreased chemotaxis and increased oxygen radical production and tissue damage.[8] Deficient suppressor T-cell numbers and activity and an imbalance in helper T cell type 1 (TH1) and helper T cell type 2 (TH2) also may play a role in an abnormal response.[9]

Although the cytokine dysregulation seems to play a role in its pathophysiology, the causative gene has not yet been identified.[10] In one study, no unique polymorphisms or mutations were found in candidate genes from the toll-like receptor pathway.[11] A significantly large number of immunoglobulin-related genes were found to be up-regulated in this syndrome. Perhaps the distinct patterns may facilitate understanding of its pathophysiology and, possibly, its diagnosis.

The hyper-IgE syndromes have multiple genetic bases. The majority of patients have dominant mutations in the signal transducer and activator of transcription 3 (STAT3) gene STAT3.[12] Autosomal recessive mutations in DOCK8 are linked with the autosomal recessive hyper-IgE syndrome. Dominant-negative mutations in STAT3 gene have been associated with the classic multisystem form of hyper-IgE syndrome.[13]

Hyper-IgE syndrome may be associated with defective salivary activity, which accounts for the enhanced susceptibility of these patients to oral candidiasis.[14]

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Epidemiology

Frequency

International

Job syndrome (HIE syndrome, or hyper-IgE syndrome) is a rare disorder; about 250 cases have been published.

Mortality/Morbidity

Significant morbidity is associated with Job syndrome (HIE syndrome, or hyper-IgE syndrome). The vast majority of patients have severe cutaneous and pulmonary disease, and most patients have multiple bone fractures and scoliosis. The mortality rate is elevated because of systemic infections.

Race

Job syndrome (HIE syndrome, or hyper-IgE syndrome) occurs in people of diverse ethnic backgrounds and does not seem to be more common in any specific population.

Sex

No sex predilection is reported for Job syndrome (HIE syndrome, or hyper-IgE syndrome).

Age

Job syndrome (HIE syndrome, or hyper-IgE syndrome) usually commences in infancy, but diagnosis is often delayed until childhood or even adulthood.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Mordechai M Tarlow, MD  Clinical Associate, Department of Dermatology, University of Pennsylvania School of Medicine

Mordechai M Tarlow, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for MOHS Surgery, American Society of Cosmetic Dermatology and Aesthetic Surgery, and Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

Bernice R Krafchik, MBChB, FRCPC  Professor Emeritus, Department of Pediatrics, Section of Dermatology, University of Toronto

Bernice R Krafchik, MBChB, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Royal College of Physicians and Surgeons of Canada, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD  Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Glen H Crawford, MD  Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. Grimbacher B, Holland SM, Puck JM. Hyper-IgE syndromes. Immunol Rev. Feb 2005;203:244-50. [Medline].

  2. Minegishi Y, Karasuyama H. Genetic origins of hyper-IgE syndrome. Curr Allergy Asthma Rep. Sep 2008;8(5):386-91. [Medline].

  3. Ma CS, Chew GY, Simpson N, et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med. Jul 7 2008;205(7):1551-7. [Medline].

  4. van de Veerdonk FL, Marijnissen R, Joosten LA, et al. Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency. Clin Exp Immunol. Jan 2010;159(1):57-64. [Medline].

  5. Stiehm ER. Cytokine dysregulation in the hyperimmunoglobulinemia E syndrome. J Pediatr. Feb 2000;136(2):141-3. [Medline].

  6. Paslin D, Norman ME. Atopic dermatitis and impaired neutrophil chemotaxis in Job's syndrome. Arch Dermatol. Jun 1977;113(6):801-5. [Medline].

  7. Simon HU, Seger R. Hyper-IgE syndrome associated with an IL-4-producing gamma/delta(+) T-cell clone. J Allergy Clin Immunol. Jan 2007;119(1):246-8. [Medline].

  8. Vargas L, Patino PJ, Rodriguez MF, et al. Increase in granulocyte-macrophage-colony-stimulating factor secretion and the respiratory burst with decreased L-selectin expression in hyper-IgE syndrome patients. Ann Allergy Asthma Immunol. Sep 1999;83(3):245-51. [Medline].

  9. Shirafuji Y, Matsuura H, Sato A, Kanzaki H, Katayama H, Arata J. Hyperimmunoglobin E syndrome: a sign of TH1/TH2 imbalance?. Eur J Dermatol. Mar 1999;9(2):129-31. [Medline].

  10. Tanaka T, Takada H, Nomura A, Ohga S, Shibata R, Hara T. Distinct gene expression patterns of peripheral blood cells in hyper-IgE syndrome. Clin Exp Immunol. Jun 2005;140(3):524-31. [Medline].

  11. Hawn TR, Ozinsky A, Williams LM, et al. Hyper-IgE syndrome is not associated with defects in several candidate toll-like receptor pathway genes. Hum Immunol. Jul 2005;66(7):842-7. [Medline].

  12. Engelhardt KR, McGhee S, Winkler S, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. Dec 2009;124(6):1289-302.e4. [Medline].

  13. Minegishi Y. Hyper-IgE syndrome. Curr Opin Immunol. Oct 2009;21(5):487-92. [Medline].

  14. Conti HR, Baker O, Freeman AF, Jang WS, Holland SM, Li RA, et al. New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome. Mucosal Immunol. Feb 23 2011;[Medline].

  15. Vigliante CE, Costello BJ, Quinn PD. Life-threatening cervicofacial infection in a child with hyperimmunoglobulin-E syndrome. J Oral Maxillofac Surg. May 2001;59(5):561-5. [Medline].

  16. 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. Feb 2000;89(2):177-85. [Medline].

  17. Onal IK, Kurt M, Altundag K, Aksoy S, Dincer M, Gullu I. Peripheral T-cell lymphoma and Job's syndrome: a rare association. Med Oncol. 2006;23(1):141-4. [Medline].

  18. Ling JC, Freeman AF, Gharib AM, et al. Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Clin Immunol. Mar 2007;122(3):255-8. [Medline].

  19. Sarmento KM Jr, Tomita S, Caliman e Gurgel JD. Association between nasal polyposis, Dubowitz syndrome and hyper-IgE syndrome. Int J Pediatr Otorhinolaryngol. May 2008;72(5):711-4. [Medline].

  20. Borges WG, Hensley T, Carey JC, Petrak BA, Hill HR. The face of Job. J Pediatr. Aug 1998;133(2):303-5. [Medline].

  21. Freeman AF, Domingo DL, Holland SM. Hyper IgE (Job's) syndrome: a primary immune deficiency with oral manifestations. Oral Dis. Jan 2009;15(1):2-7. [Medline].

  22. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. Mar 4 1999;340(9):692-702. [Medline].

  23. Grimbacher B, Schaffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. Sep 1999;65(3):735-44. [Medline].

  24. 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. Sep 2010;126(3):611-7.e1. [Medline].

  25. Kumanovics 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. Jan 21 2010;[Medline].

  26. Ge AX, Ryan ME, Holland SM, et al. Acupuncture for symptom management in patients with hyper-IgE (Job's) syndrome. J Altern Complement Med. Jan 2011;17(1):71-6. [Medline]. [Full Text].

  27. Tanaka H, Ito R, Onodera N, Waga S. Efficacy of long-term sulfamethoxazole-trimethoprim therapy in a boy with hyperimmunoglobulin E syndrome. Tohoku J Exp Med. Sep 1998;186(1):61-6. [Medline].

  28. Kojima K, Inoue Y, Katayama Y, et al. Improvement with disodium cromoglycate of neutrophil phagocytosis and respiratory burst activity in a patient with hyperimmunoglobulin E syndrome. Allergy. Nov 1998;53(11):1101-3. [Medline].

  29. Wakim M, Alazard M, Yajima A, Speights D, Saxon A, Stiehm ER. High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol. Aug 1998;81(2):153-8. [Medline].

  30. Bittner TC, Pannicke U, Renner ED, et al. Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation. Klin Padiatr. Nov 2010;222(6):351-5. [Medline].

  31. Ge AX, Ryan ME, Holland SM, et al. Acupuncture for symptom management in patients with hyper-IgE (Job's) syndrome. J Altern Complement Med. Jan 2011;17(1):71-6. [Medline]. [Full Text].

  32. Hori J, Yamaguchi S, Watanabe M, Osanai H, Hori M. Fournier gangrene associated with hyper IgE syndrome (Job syndrome). Int J Urol. Apr 2008;15(4):372-3. [Medline].

  33. Kumanovics A, Perkins SL, Gilbert H, Cessna MH, Augustine NH, Hill HR. Diffuse large B cell lymphoma in hyper-IgE syndrome due to STAT3 mutation. J Clin Immunol. Nov 2010;30(6):886-93. [Medline].

 
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