History

Eczematoid dermatitis starts in the newborn period and is typically associated with and driven by Staphylococcus aureus infection. Skin abscesses due to S aureus are common and typically not associated with a robust inflammatory response either locally or systemically, hence the term cold abscesses. Mucocutaneous candidiasis, including onychomycosis, occurs frequently. Conversely, severe warts and Molluscum species are not features of autosomal dominant hyper-IgE syndrome (AD-HIES).

Pneumonias start in early childhood, typically due to S aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Similar to the skin abscesses, signs of systemic toxicity are modest. Even when treated aggressively and promptly, the pneumonias often resolve with pneumatocele formation (see image below), presumably due to dysregulated local inflammation and resultant tissue destruction. Later superinfection of the pneumatoceles with Pseudomonas aeruginosa and molds such as Aspergillus and Scedosporium species can be associated with significant morbidity and mortality. Opportunistic infections including Pneumocystis jiroveci pneumonia, disseminated histoplasmosis, cryptococcosis, and coccidioidomycosis also occur, although less frequently. Recurrent bacterial sinusitis and otitis are common, but susceptibility to viral pathogens is not increased.

Recurrent pneumonias, particularly those due to S aureus, may lead to pneumatocele formation. Pneumatoceles such as those demonstrated in this CT image may then allow fungal superinfection.

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AD-HIES is also associated with multiple connective tissue and skeletal abnormalities, including scoliosis, hyperextensibility, pathologic fractures, retained primary dentition, craniosynostosis, and vascular abnormalities. Many patients have hyperextensibility of at least one joint. Despite these connective tissue abnormalities, AD-HIES patients typically demonstrate normal wound healing. Most patients report at least one nontraumatic fracture, such as broken ribs with coughing. Osteoporosis is common but does not appear to correlate with frequency of fractures. Retention of primary teeth is due to failure of primary tooth exfoliation;^[13]characteristic palatal, tongue, and oral mucosal changes are often present as well. Arterial tortuosity and aneurysm occur, typically of the middle-sized vessels, such as coronary arteries.^{[14, 15]}Brain MRI abnormalities include focal hyperintensities and an increased incidence of Chiari I malformations.^[16]

Despite the increased IgE and eosinophilia, patients do not typically have significant atopy with regard to foods or seasonal allergens.

A detailed family history may help identify other cases, but most cases are spontaneously arising mutations or autosomal dominant. The clinical diagnosis of AD-HIES has been based on a composite profile of immunologic and nonimmunologic features, leading to a score that correlates well with identifying STAT3 mutations.

Physical

Individuals with autosomal dominant hyper-IgE syndrome (AD-HIES) share a characteristic facial appearance, with a broad nose, deep-set eyes with prominent forehead, and generalized coarsening of the facial features with age. A high arched palate is often present, and double-rowed teeth may be present. Oral thrush may be seen. The tympanic membrane may be scarred from recurrent otitis.

Both pediatric and adult patients may demonstrate an erythematous, scaly pruritic rash, typical of eczematous dermatitis. Scarring from incision and drainage of boils may be present. The nails, vagina, and inguinal region often demonstrate candidiasis.

The pulmonary examination varies depending on previous pulmonary infections and lung parenchymal changes. The examination ranges from normal to decreased tactile fremitus and decreased air exchange associated with large pneumatoceles. Clubbing of the nails is common.

Scoliosis >10 degrees is seen in 60% of patients. Hyperextensibility of at least one joint is present in 70% of patients.

Causes

Most, if not all, cases of autosomal dominant hyper-IgE syndrome (AD-HIES) are due to dominant negative mutations in STAT3, a key signaling molecule for immunologic and somatic gene transcription.

Differential Diagnoses

Davis SD, Schaller J, Wedgwood RJ. Job's Syndrome. Recurrent, "cold", staphylococcal abscesses. Lancet. 1966 May 7. 1(7445):1013-5. [QxMD MEDLINE Link].
Sowerwine KJ, Holland SM, Freeman AF. Hyper-IgE syndrome update. Ann N Y Acad Sci. 2012 Feb. 1250:25-32. [QxMD MEDLINE Link].
Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972 Jan. 49(1):59-70. [QxMD MEDLINE Link].
Grimbacher B, Holland SM, Puck JM. Hyper-IgE syndromes. Immunol Rev. 2005 Feb. 203:244-50. [QxMD MEDLINE Link].
Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007 Aug 30. 448(7157):1058-62. [QxMD MEDLINE Link].
Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007 Oct 18. 357(16):1608-19. [QxMD MEDLINE Link].
Sowerwine KJ, Holland SM, Freeman AF. Hyper-IgE syndrome update. Ann N Y Acad Sci. 2012 Feb. 1250:25-32. [QxMD MEDLINE Link].
Chandesris MO, Melki I, Natividad A, Puel A, Fieschi C, Yun L, et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore). 2012 Jul. 91(4):e1-19. [QxMD MEDLINE Link].
Minegishi Y, Saito M. Molecular mechanisms of the immunological abnormalities in hyper-IgE syndrome. Ann N Y Acad Sci. 2011 Dec. 1246:34-40. [QxMD MEDLINE Link].
Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008 Apr 10. 452(7188):773-6. [QxMD MEDLINE Link]. [Full Text].
Freeman AF, Kleiner DE, Nadiminti H, Davis J, Quezado M, Anderson V. Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol. 2007 May. 119(5):1234-40. [QxMD MEDLINE Link].
Leonard GD, Posadas E, Herrmann PC, Anderson VL, Jaffe ES, Holland SM. Non-Hodgkin's lymphoma in Job's syndrome: a case report and literature review. Leuk Lymphoma. 2004 Dec. 45(12):2521-5. [QxMD MEDLINE Link].
O'Connell AC, Puck JM, Grimbacher B, Facchetti F, Majorana A, Gallin JI, et al. Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Feb. 89(2):177-85. [QxMD MEDLINE Link].
Ling JC, Freeman AF, Gharib AM, Arai AE, Lederman RJ, Rosing DR. Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Clin Immunol. 2007 Mar. 122(3):255-8. [QxMD MEDLINE Link].
Freeman AF, Avila EM, Shaw PA, Davis J, Hsu AP, Welch P, et al. Coronary artery abnormalities in Hyper-IgE syndrome. J Clin Immunol. 2011 Jun. 31 (3):338-45. [QxMD MEDLINE Link].
Freeman AF, Collura-Burke CJ, Patronas NJ, et al. Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics. 2007 May. 119(5):e1121-5. [QxMD MEDLINE Link].
Ozcan E, Notarangelo LD, Geha RS. Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol. 2008 Dec. 122(6):1054-62; quiz 1063-4. [QxMD MEDLINE Link].
Jonczyk-Potoczna K, Szczawinska-Poplonyk A, Warzywoda M, Breborowicz A, Pawlak B. Hyper Ig E syndrome (Job syndrome, HIES) - radiological images of pulmonary complications on the basis of three cases. Pol J Radiol. 2012 Apr. 77(2):69-72. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

STAT3 gene is diagrammed with depiction of hotspots (areas where higher numbers of patients were noted to have mutations).
HIES scoring sheet. A score >40 is considered likely HIES, 20-40 indeterminate, < 20 unlikely HIES.
Recurrent pneumonias, particularly those due to S aureus, may lead to pneumatocele formation. Pneumatoceles such as those demonstrated in this CT image may then allow fungal superinfection.
Brain hyperintensities have been noted to be present with increased frequency in patients of all ages with Job syndrome.

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Table. Scoring System for Job Syndrome

Table. Scoring System for Job Syndrome

	0	1	2	3	4	5	6	7	8	10
Clinical Findings
Highest IgE (IU/mL)	< 200	200-500			501-1000				1001-2000	>2000
Total # skin abscesses/boils	None		1-2		3-4				>4
Total # pneumonias	None		1		2		3		>3
Parenchymal lung abnormalities	None						Bronchiectasis		Pneumatocele
Other serious infection	None				Present
Fatal infection	None				Present
Highest eosinophils/uL	< 700			701-800			>800
Newborn rash	None				Present
Eczema (worst stage)	None	Mild	Moderate		Severe
Sinusitis/otitis (# in worst year)	1-2	3	4-6		>6
Candidiasis	None	Oral, vaginal	Fingernail		Systemic
Retained primary teeth	None	1	2		3				>3
Scoliosis (max. curvature)	< 10		10-14		15-20				>20
Minimal trauma fractures	None				1-2				>2
Hyperextensibility	None				Present
Characteristic face	None		Mild			Present
Increased interalar distance	< 1 SD	1-2 SD		>2 SD
High palate	None		Present
Congenital anomaly	None					Present
Lymphoma	None				Present

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Author

Jennifer Heimall, MD Clinical Fellow, Department of Allergy and Immunology, National Institutes of Health-NIAID

Jennifer Heimall, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, American College of Physicians-American Society of Internal Medicine, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Alexandra Freeman, MD Staff Clinician, Laboratory of Clinical Infectious Diseases, NIAID, NIH

Alexandra Freeman, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Steven M Holland, MD Assistant Professor of Medicine, Department of Medicine, Johns Hopkins Hospital; Chief, Laboratory of Clinical Infectious Diseases, Chief, Infectious Diseases Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Steven M Holland, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Charles H Kirkpatrick, MD

Charles H Kirkpatrick, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Physicians, American Society for Clinical Investigation, Clinical Immunology Society, American Federation for Clinical Research

Disclosure: Received consulting fee from Dyax for consulting.

Acknowledgements

The authors would like to acknowledge the patients with HIES and their families who have generously aided in our understanding of this fascinating syndrome.