Laboratory Studies

CBC with differential is used to assess absolute eosinophil count in patients with autosomal dominant hyper-IgE syndrome (AD-HIES). Eosinophilia usually accompanies the IgE elevation but is not correlated with it. Absolute lymphocyte counts are usually normal, and lymphocyte subsets do not need to be obtained for routine clinical care. Anemia and thrombocytopenia are not typically associated with AD-HIES.

Quantitative serum immunoglobulins IgG, IgA, IgM, IgE: the serum IgE is typically >2000 IU/mL, while other immunoglobulin levels are normal. However, IgE level normalizes in adulthood in about 20% of cases.

Qualitative immunoglobulins to specific antigens may be useful in patients with severe sinopulmonary disease and in those who develop recurrent infections despite effective use of antimicrobial prophylaxis. Some patients with HIES have decreased specific antibody responses to vaccines for Haemophilus influenzae type b (HiB), Streptococcus pneumoniae, tetanus, or diphtheria.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are useful if levels are elevated, but normal ESR and CRP levels do not rule out bacterial infection.

Electrolytes, coagulation, renal and hepatic function studies are not affected in HIES.

Skin abscesses should be incised and drained; obtain cultures of drainage.

When lung infection is present, sputum should be obtained through routine collection, sputum induction, or bronchoscopy.

STAT3 mutation analysis should be performed to confirm a high clinical suspicion of AD-HIES.

Imaging Studies

Chest x-ray, chest CT, or both are necessary to determine the extent of pulmonary parenchymal involvement in autosomal dominant hyper-IgE syndrome (AD-HIES).^[18]See image below.

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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X-rays should be taken of the spine to assess scoliosis.

Complaints of bone or joint paint should be assessed radiologically because of the increased risk of pathologic fractures in these patients.

Vascular abnormalities are usually asymptomatic, including intracranial aneurysms and coronary artery ectasia, tortuosity, and aneurysms. These anomalies are common, as detected by CT and MRI in research studies.

X-ray or MRI studies of the skull often show craniosynostosis.

MRI of the brain usually shows T2-weighted hyperintensities, an increased prevalence of lacunar infarcts, and an increased rate of Chiari type 1 malformations. See image below.

Brain hyperintensities have been noted to be present with increased frequency in patients of all ages with Job syndrome.

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Other Tests

Pulmonary function tests, including diffusing capacity of lung for carbon monoxide (DLCO), provide baseline pulmonary status in patients with autosomal dominant hyper-IgE syndrome (AD-HIES).

Treatment & Management

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.