Hyper IgE Syndrome

Background

This is a rare immunodeficiency characterized by recurrent staphylococcal infection of the skin, lung infections, atopic dermatitis, and high serum levels of IgE. These patients are also at increased risk of osteoporosis and spontaneous bone fractures. It is inherited as an autosomal dominant disease.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS Buckley syndrome
Job's syndrome

INCIDENCE Rare

GEOGRAPHY

WAORANI INDIANS

Hyperimmunoglobulinemia E in the Waorani, an isolated Amerindian population.

Kaplan JE, Larrick JW, Yost JA.
Am J Trop Med Hyg 1980 Sep;29(5):1012-7 Abstract quote
The Waorani Indians of Eastern Ecuador have the highest blood levels of immunoglobulin E that have been recorded in a human population.

Using a radial immunodiffusion technique for IgE determination, we found the mean plasma IgE concentration for the entire sample (n = 227) to be 11,975 International Units per milliliter (normal: 5--500 IU/ml). The reason for the elevated IgE concentrations is unclear, although genetic factors and a high prevalence of parasitic infection may be involved. Atopic disease is rare among the Waorani as determined by medical history, physical examination, and immediate hypersensitivity skin tests.

Our data are consistent with the association between hyperimmunoglobulinemia E and low prevalence of atopic disease in tropical populations. The significance of the findings with regard to the control of allergic disorders is discussed.

DISEASE ASSOCIATIONS CHARACTERIZATION

ATOPIC DERMATITIS

Dermatitis and the Newborn Rash of Hyper-IgE Syndrome
Cheryl Lee D. Eberting, MD; Joie Davis, APRN, APNG; Jennifer M. Puck, MD; Steven M. Holland, MD; Maria L. Turner, MD

From the Dermatology Branch, Center for Cancer Research, National Cancer Institute (Drs Eberting and Turner), the National Human Genome Research Institute (Ms Davis and Dr Puck), and the National Institute of Allergy and Infectious Diseases (Dr Holland), Bethesda, Md. The authors have no relevant financial interest in this article.

Arch Dermatol. 2004;140:1119-1125. Abstract quote Objective To characterize the dermatitis, the newborn rash, and cutaneous findings in hyper-IgE syndrome, also known as Job's syndrome.
Design Prospective and retrospective evaluation and treatment of cutaneous manifestations in patients with a clinical diagnosis of hyper-IgE syndrome (HIES). Analysis of the newborn rash encountered in this population.
Setting Dermatology clinic at the National Institutes of Health, Bethesda, Md.
Patients Forty-three patients seen in our clinic between January 1998 and August 2003 who had a clinical diagnosis of HIES.
Interventions The UK Working Party's Diagnostic Criteria for Atopic Dermatitis were used to assess for atopic dermatitis in this population. To assess the newborn rash, we performed a retrospective chart review and an in-person or telephone interview of the parent or caregiver of each patient.
Results Twenty-eight (65%) of 43 patients fulfilled the criteria for atopic dermatitis. Thirty-five (81%) of 43 patients reported a newborn rash. Eight (19%) of 43 were born with the rash; 23 (53%) of 43 had acquired the rash within 7 days; 32 (74%) of 43 within 14 days; 34 (79%) of 43 within 30 days; and 35 (81%) of 43 had the rash within 35 days of birth.
Conclusions The dermatitis in HIES resembles classic atopic dermatitis but may have distinctive features. A newborn rash is almost always a presenting sign of HIES. After the newborn period, skin findings include retroauricular fissures, external otitis, infected dermatitis of the axillae and groin, folliculitis of the upper back and shoulders, cutaneous abscesses, mucocutaneous candidiasis, and in some patients pitted scarring of the face.

Atopic dermatitis and impaired neutrophil chemotaxis in Job's syndrome.

Paslin D, Norman ME.

Arch Dermatol 1977 Jun;113(6):801-5 Abstract quote
A 22-year-old white woman with Job's syndrome was found to have atopic dermatitis and impaired neutrophil chemotaxis in vitro. Major clinical features of Job's syndrome included large, "cold" and recurrent staphylococcal abscesses, and intermittent bacterial and yeast infections.

Evidence for atopic disease included infantile eczema progressing to flexural dermatitis, a family history of atopy, positive immediate hypersensitivity skin tests, and hyperimmunoglobulinemia E. Defective erythema responses to histamine, methyl niacinate, and methacholine (Mecholyl) chloride may explain the lack of redness, heat, or pain signalling the development of abscesses (hence the term "cold"). Impaired chemotaxis was probably due to an intrinsic neutrophil defect since patient's serum generated normal amounts of chemotactic factors and did not contain an inhibitor of neutrophil chemotaxis.

A delay in neutrophil exudation in vivo may explain the abscess formations and the atopic diathesis may explain the absence of clinical signs of inflammation that have been described in this and other patients with Job's syndrome.

HERPES SIMPLEX INFECTION

Herpes simplex virus infection in a hyper-IgE patient: appearance of unusual mass lesions.

Hershko K, Hershko AY, Leibovici V, Meir K, Ingber A.

Department of Dermatology, Hadassah University Hospital, Jerusalem, Israel.
Acta Derm Venereol. 2002;82(3):204-5. Abstract quote
A 7-year-old girl presented with large soft masses rising from the nostril and from behind the ear. She had previously been diagnosed as suffering from hyper-IgE syndrome.

The presence of herpes simplex virus infection within these lesions was confirmed by biopsy and immunohistochemical studies. The mass lesions did not respond to antibacterial therapy with cefazolin, but improved promptly under antiviral therapy with acyclovir. Immunological studies revealed a mild decrease in the CD4 cell population.

Based on our results and on the relevant literature we propose an immunological mechanism for this unique manifestation of herpes simplex virus infection in hyper-IgE syndrome.

HIV INFECTION

Hyper-IgE and human immunodeficiency virus infection.

Lin RY, Smith JK Jr.

Department of Medicine, Metropolitan Hospital, NYMC, NY.

Ann Allergy 1988 Oct;61(4):269-72 Abstract quote
A 39-year-old black male who is an intravenous drug abuser developed certain clinical manifestations that were consistent with the hyper-IgE syndrome. These included an extremely elevated IgE (greater than 2000 IU/mL), extensive eczematoid dermatitis, and recurrent soft tissue infections. He had no history of atopic disease as a child. Immunophenotypic analysis of peripheral blood mononuclear cells showed a significant decrease in helper (CD 4) cells with a normal concentration of suppressor (CD 8) cells. Human immunodeficiency virus (HIV) antibody was detected in his serum.

Previous studies of patients with atopic dermatitis as well as of patients with the hyper-IgE syndrome characteristically show decreases in total suppressor lymphocyte concentrations in peripheral blood. These results led some investigators to postulate that high IgE concentrations in patients with atopic dermatitis result from defective IgE specific suppression. More recent evidence suggests that helper cell function may be the more critical impairment in these disorders.

The development of a hyper-IgE syndrome in this setting of T-helper cell viral affliction lends further support to the hypothesis that helper lymphocyte defects may have a key role in the development of atopic dermatitis and the hyper-IgE syndrome.

OSTEOCHONDRITIS DISSECANS

Osteochondritis dissecans in a patient with hyperimmunoglobulin E syndrome.

Kilic SS, Sanal O, Tezcan I, Ersoy F.

Department of Pediatrics, Uludag University Faculty of Medicine, Bursa, Turkey.

Turk J Pediatr. 2002 Oct-Dec;44(4):357-9. Abstract quote
Hyperimmunoglobulin E syndrome (hyper-IgE) is a rare immunodeficiency disease associated with recurrent pyogenic infections, chronic eczematoid dermatitis and osteopenia.

We present here a 13-year-old girl with hyperimmunoglobulin E syndrome, who developed osteochondritis dissecans (OCD) of the lateral femoral condyle, which is rare.

Osteopenia, which is frequently associated with hyper IgE, may predispose the patient to the development of OCD.

PREGNANCY

Hyperimmunoglobulinemia E and pregnancy: a case report.

Lindenbaum C, Chatwani A, Oyer R, Fitzgerald J.

Department of Obstetrics and Gynecology, Temple University Hospital, Philadelphia, PA 19140.

Am J Obstet Gynecol 1987 Nov;157(5):1273-4 Abstract quote
Hyperimmunoglobulinemia E is characterized by recurrent bacterial sinopulmonary and skin infections from birth or early childhood, with IgE levels at least 10 times greater than the upper limits of normal.

The following case describes a young black woman with hyperimmunoglobulinemia E syndrome who had an uneventful pregnancy and delivery. The infant has been diagnosed as suffering from hyperimmunoglobulinemia E syndrome as well.

PATHOGENESIS CHARACTERIZATION

CYTOKINES

Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome.

Borges WG, Augustine NH, Hill HR.

Departments of Pathology, Pediatrics, and Medicine, University of Utah School of Medicine, and the ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84132, USA.
J Pediatr 2000 Feb;136(2):176-80 Abstract quote
OBJECTIVE: Patients with the hyperimmunoglobulinemia E (hyper-IgE) syndrome are reported to have defective production of interferon gamma (IFN-gamma). Because IFN-gamma is a major activator of polymorphonuclear leukocytes (PMNs), this could result in defective PMN chemotaxis and markedly elevated IgE levels because of the unopposed action of interleukin (IL)-4. IL-12, an important enhancer of IFN-gamma production, also suppresses IgE production. This study assessed the IL-12/IFN-gamma pathway in patients with hyper-IgE syndrome.

METHODS: Production of IL-12 and IFN-gamma by mononuclear cells from 10 patients with hyper-IgE syndrome in response to a number of stimuli was determined, as well as the effect of IL-12 on IFN-gamma release and cell proliferation.

RESULTS: IL-12 and IFN-gamma production by the patients' cells was similar to that of control subjects independent of the stimulus used, except for Staphylococcus aureus, with which cells of patients with hyper-IgE syndrome released markedly less IFN-gamma (19.8%; P <.002). The ability of recombinant IL-12 to enhance IFN-gamma release from patients' cells in response to all stimuli was, however, significantly lower than with control cells (12% to 51%; P <.03).

CONCLUSION: The lymphocytes of patients with hyper-IgE syndrome have an impaired response to IL-12, resulting in decreased IFN-gamma production, which may be of key importance in the pathogenesis of the immune abnormalities of hyper-IgE syndrome.

IgE RECEPTOR

IgE Fc receptor positive T, B and NK cells in patients with the hyper-IgE syndrome.

Spiegelberg HL, Thompson LF, McNeil D, Buckley RH.

Int Arch Allergy Appl Immunol 1985;77(1-2):277-9 Abstract quote
Patients with the hyper-IgE syndrome have greatly elevated percentages of IgE Fc receptor (Fc epsilon R)-positive B cells, but they have less than 0.1% Fc epsilon R+ T cells (T epsilon cells) and few, if any, Fc epsilon R+ natural killer cells. They also have markedly decreased numbers of IgG receptor positive (Fc gamma R+) T cells (T gamma cells).

Patients with the hyper-IgE syndrome resemble in this respect patients with severe atopic dermatitis. Since a portion of T epsilon and T gamma cells of mildly atopic patients react with monoclonal antibody OKT8, they may have a suppressor function. However, whether the low number of T epsilon cells is responsible for the high IgE serum level in hyper-IgE syndrome and atopic dermatitis patients remains to be demonstrated.

Attempts to obtain a reliable assay for human IgE synthesis in vitro to investigate the function of Fc epsilon R-positive lymphocytes proved to be difficult.

Even isolated B cells from atopic donors seldom produced more than twice the quantity of IgE released from cells incubated in the presence of the protein synthesis inhibitor cycloheximide.

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

Hyperimmunoglobulinemia E syndrome: radiographic observations.

Merten DF, Buckley RH, Pratt PC, Effmann EL, Grossman H.
Radiology 1979 Jul;132(1):71-8 Abstract quote
Susceptibility to recurrent staphylococcal cutaneous and respiratory infections beginning in infancy associated with extreme hyperimmunoglobulinemia E is a recently described primary immunodeficiency syndrome. Other clinical features include depressed cellular immunity and deficient antibody formation.

Recurrent pneumonia and cyst formation with variable persistence and expansion characterized the radiographic couse in 11 patients.

Five cysts resolved with continuous antistaphylococcal therapy; 2 were resected without recurrence; and 4 persisted after surgery and/or antibiotics (2--8 years). The cysts had dense, necrotic surfaces with fibrous walls, eosinophilic and other inflammatory cell infiltrates, and frequent, persistent, bronchial connections. Sinusitis (9/9) and mastoiditis (3/4) were also observed radiographically.

LABORATORY MARKERS

LEUKOCYTE CHEMOTAXIS

Severe staphylococcal disease associated with allergic manifestations, hyperimmunoglobulinemia E, and defective neutrophil chemotaxis.

Hill HR, Estensen RD, Hogan NA, Quie PG.
J Lab Clin Med 1976 Nov;88(5):796-806 Abstract quote
Neutrophil granulocyte function was determined in three patients with systemic staphylococcal infection, clinical manifestations of generalized allergic disease, and hyperimmunoglobulinemia E.

Each of the patients had urticarial skin rashes before or at the time of development of staphylococcal suppurative lymphadenitis, pneumonia, or sepsis. Neutrophil chemotaxis, random migration, phagocytosis, and bactericidal capacity were assessed to determine if an abnormality in these functions might have contributed to the development of severe staphylococcal infections.

Each of the three patients with generalized urticaria was found to have a marked defect in neutrophil chemotaxis. The mean chemotactic index of the patients was 12 +/- 4, whereas that of 20 controls was 72 +/- 11. Neutrophil random migration, phagocytosis, and bactericidal capacity were normal in each patient. The serum or plasma of the patients did not inhibit chemotaxis of control neutrophils and did not contain an increased concentration of the chemotactic-factor inactivator found in normal serum.

Treatment of the neutrophils of these three patients with the competitive histamine H2 receptor blocking agent, burimamide, produced a significant increase in chemotactic responsiveness. These studies suggest the possibility of pharmacologic modification of neutrophil granulocyte function.

A hyperimmunoglobulin E syndrome with normal chemotaxis in vitro and defective leukotaxis in vivo.

Weston WL, Humbert JR, August CS, Harnett J, Mass MF, Dean PB, Hagen IM.
J Allergy Clin Immunol 1977 Feb;59(2):115-9 Abstract quote
A 26-yr-old male with a lifelong history of atopic dermatitis and recurrent severe staphylococcal abscesses was found to have hyperimmunoglobulinemia E. Evaluation of both the humoral and cellular aspects of chemotaxis in vitro showed both neutrophils and monocytes to be normal.

However, quantitative neutrophil migration in vivo was significantly suppressed using the patient's own serum as the attractant. This defective migration in vivo was partially corrected by serum from normal donors as the attractant and also partially corrected following plasma infusion in this patient.

Evaluation of quantitative leukocyte migration in vivo may be most useful in patients suspected of defects of leukocyte mobility.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Hyperimmunoglobulin E syndrome: two cases and a review of the literature.

DeWitt CA, Bishop AB, Buescher LS, Stone SP.

Division of Dermatology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.

J Am Acad Dermatol. 2006 May;54(5):855-65. Abstract quote

Hyperimmunoglobulin E syndrome (HIES) is a rare immunodeficiency associated with elevated serum IgE levels, eczematous skin, recurrent cutaneous infections, and distinctive musculoskeletal features.

We report two cases seen at our institution and review the current literature. Patient 1 was an 18-month-old African American boy with recurrent staphylococcal cold abscesses, pneumonia, and bacteremia. He had severely eczematous skin, ultimately complicated by eczema herpeticum. After treatment of systemic infections with culture-directed antibiotics, a brief course of cyclosporine, 5 mg/kg, improved the dermatitis and allowed transition to long-term therapy with oral trimethoprim-sulfamethoxazole. Patient 2 was a 15-year-old Caucasian boy with long-standing HIES. He has been maintained on a regimen of interferon gamma injections given 3 times weekly and monthly intravenous immunoglobulin since the age of 3 years, prophylactic antibiotics, and low-dose fluconazole.

He has occasional episodes of cold abscesses and sinusitis, but has had excellent control since institution of this regimen and has not experienced any adverse effects.

Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder.
Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4442, USA.

N Engl J Med 1999 Mar 4;340(9):692-702 Abstract quote
BACKGROUND: The hyper-IgE syndrome with recurrent infections is a rare immunodeficiency characterized by recurrent skin and pulmonary abscesses and extremely elevated levels of IgE in serum. Associated facial and skeletal features have been recognized, but their frequency is unknown, and the genetic basis of the hyper-IgE syndrome is poorly understood.

METHODS: We studied 30 patients with the hyper-IgE syndrome and 70 of their relatives. We took histories, reviewed records, performed physical and dental examinations, took anthropometric measurements, and conducted laboratory studies.

RESULTS: Nonimmunologic features of the hyper-IgE syndrome were present in all patients older than eight years. Seventy-two percent had the previously unrecognized feature of failure or delay of shedding of the primary teeth owing to lack of root resorption. Common findings among patients were recurrent fractures (in 57 percent of patients), hyperextensible joints (in 68 percent), and scoliosis (in 76 percent of patients 16 years of age or older). The classic triad of abscesses, pneumonia, and an elevated IgE level was identified in 77 percent of all patients and in 85 percent of those older than eight. In 6 of 23 adults (26 percent), IgE levels declined over time and came closer to or fell within the normal range. Autosomal dominant transmission of the hyper-IgE syndrome was found, but with variable expressivity. Of the 27 relatives at risk for inheriting the hyper-IgE syndrome, 10 were fully affected, 11 were unaffected, and 6 had combinations of mild immunologic, dental, and skeletal features of the hyper-IgE syndrome.

CONCLUSIONS: The hyper-IgE syndrome is a multisystem disorder that affects the dentition, the skeleton, connective tissue, and the immune system. It is inherited as a single-locus autosomal dominant trait with variable expressivity.

A patient with hyper-IgE syndrome: A multisystem disorder.

Hinrichs R, Fricke O, Tutuncu R, Hunzelmann N, Krieg T, Scharffetter-Kochanek K.

Department of Dermatology, Center of Pediatric Endocrinology and Metabolism, Children's Hospital, and Department of Operative Dentistry and Periodontology, University of Cologne.
J Am Acad Dermatol 2002 Nov;47(5 Suppl):S268-9 Abstract quote
A patient with hyper-IgE syndrome came to our attention with an exacerbation of atopic dermatitis. The medical evaluation showed typical features of hyper-IgE syndrome and a low number of cytotoxic T cells in the peripheral blood.

This case serves as a reminder that hyper-IgE syndrome is a multisystem disorder.

VARIANTS

DENTAL

Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome.

O'Connell AC, Puck JM, Grimbacher B, Facchetti F, Majorana A, Gallin JI, Malech HL, Holland SM.

National Institutes of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD 20892-1190, USA.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000 Feb;89(2):177-85 Abstract quote
OBJECTIVE: To determine the incidence of abnormal tooth eruption in patients with hyperimmunoglobulinemia E (hyper-IgE) syndrome.

STUDY DESIGN: This study evaluated 34 individuals with hyper-IgE syndrome (age range, 2-40 years). A comprehensive dental history and a head and neck evaluation were performed on all patients. Dental age was assessed in patients younger than 17 years by 2 methods: (1) clinical assessment of tooth eruption and (2) a radiographic method. Relationships between the chronologic age, dental developmental age, and age at tooth eruption were determined. Other oral or dental anomalies were recorded.

RESULTS: Of patients older than 7 years, 75% reported problems with permanent tooth eruption, as evidenced by retained primary teeth or the need for elective extractions of primary teeth to allow eruption of permanent teeth. None of the patients experienced problems with eruption of primary teeth. Eruption of the first and second permanent molars also occurred on time. Dental maturity scores were established for 14 patients 17 years of age or younger. In each case, the difference between chronologic age and the estimated dental developmental age was less than 12 months; however, we found a significant discrepancy between the chronologic age and the mean age of tooth eruption in 80% of these patients when using a particular set of standardized values. Persistence of Hertwig's epithelial root sheath was observed on histologic examination. Chronic multifocal oral candidiasis was a consistent feature in patients with hyper-IgE recurrent infection syndrome. Other oral anomalies were also noted.

CONCLUSION: We confirmed that a disorder of tooth eruption is part of the hyper-IgE syndrome. This problem occurs because of delayed primary tooth exfoliation rather than a developmental delay in the formation of the permanent dentition. The persistence of Hertwig's epithelial root sheath is unusual and may be associated with the lack of resorption of the primary teeth. Dentists should be aware of this feature of hyper-IgE syndrome because timely intervention will allow normal eruption to occur.

LUNGS

Hyperimmunoglobulinemia E in a child with allergic bronchopulmonary aspergillosis and bronchiectasis.

Hart RJ, Patterson R, Sommers H
J Pediatr 1976 Jul;89(1):38-41 Abstract quote
A 12-year-old boy was hospitalized for resection of a bronchiectatic lesion. Investigation of an elevated cencentration of serum IgE led to a diagnosis of allergic bronchopulmonary aspergillosis. ABPA has rarely been described in the pediatric age group.

This hypersensitivity lung disease is characterized by intermittent wheezing, fever, recurrent pulmonary infiltrates, eosinophilia, hyperimmunoglobulinemia E, and Type I (allergic) skin reactivity to aspergillus extract. Hyphae of aspergillus may also be found in expectorated brown mucus plugs. Type III (Arthus) skin test response and presence of precipitating antibody to this fungus may be demonstrated.

Central bronchiectasis or pulmonary fibrosis may result from uncontrolled progression of this disease.

SKIN

Cutaneous manifestations of hyper-IgE syndrome in infants and children.

Chamlin SL, McCalmont TH, Cunningham BB, Esterly NB, Lai CH, Mallory SB, Mancini AJ, Tamburro J, Frieden IJ.

Department of Dermatology, University of California, San Francisco, USA.
J Pediatr. 2002 Oct;141(4):572-5. Abstract quote
We describe 8 children with hyper-IgE syndrome who had papulopustular eruption on the face and scalp in the first year of life. Seven of the 8 patients had persistent peripheral eosinophilia and 3 had leukocytosis noted before diagnosis. Skin biopsy specimens in 6 patients revealed spongiosis and perivascular dermatitis and/or folliculitis with a predominance of eosinophils.

Two patients had bone fractures and osteopenia. Recurrent pneumonia occurred in 6 children and pneumatoceles in 5. The diagnosis of hyper-IgE syndrome was made an average of 18 months after the onset of the initial papulopustular eruption. T

hese findings may lead to earlier recognition of the disease and institution of appropriate treatment.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

TREATMENT

INTRAVENOUS IMMUNOGLOBULIN

Moderate-dose intravenous immunoglobulin treatment of Job's syndrome. Case report.

Bilora F, Petrobelli F, Boccioletti V, Pomerri F.

Department of Surgery and Medicine, Padua University.

Minerva Med 2000 May-Jun;91(5-6):113-6 Abstract quote
Job's syndrome (or hyperimmunoglobulinemia E syndrome) is a rare genetic disease characterized by skin eczema, pyogenic "cold" abscesses, sinopulmonary recidivous infections and high IgE plasma concentrations. Job's syndrome treatment is not satisfactory and cases studied are still limited.

To describe the effects of IVIG therapy in a 37-year-old woman with hyper IgE syndrome and pneumonia. We measured IgE serum by immuno-fluorometric test and neutrophil chemotaxis by migration in a Boyden chamber before and after IVIG therapy. A moderate dose of IVIG resolved the clinical-radiological signs of the S. aureus bronchopneumonia and improved cytologic and biohumoral parameters.

Intravenous immunoglobulins represent a useful treatment for acute pneumonia in Job's syndrome.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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DISEASE ASSOCIATIONS	CHARACTERIZATION
ATOPIC DERMATITIS
Dermatitis and the Newborn Rash of Hyper-IgE Syndrome Cheryl Lee D. Eberting, MD; Joie Davis, APRN, APNG; Jennifer M. Puck, MD; Steven M. Holland, MD; Maria L. Turner, MD From the Dermatology Branch, Center for Cancer Research, National Cancer Institute (Drs Eberting and Turner), the National Human Genome Research Institute (Ms Davis and Dr Puck), and the National Institute of Allergy and Infectious Diseases (Dr Holland), Bethesda, Md. The authors have no relevant financial interest in this article.	Arch Dermatol. 2004;140:1119-1125. Abstract quote Objective To characterize the dermatitis, the newborn rash, and cutaneous findings in hyper-IgE syndrome, also known as Job's syndrome. Design Prospective and retrospective evaluation and treatment of cutaneous manifestations in patients with a clinical diagnosis of hyper-IgE syndrome (HIES). Analysis of the newborn rash encountered in this population. Setting Dermatology clinic at the National Institutes of Health, Bethesda, Md. Patients Forty-three patients seen in our clinic between January 1998 and August 2003 who had a clinical diagnosis of HIES. Interventions The UK Working Party's Diagnostic Criteria for Atopic Dermatitis were used to assess for atopic dermatitis in this population. To assess the newborn rash, we performed a retrospective chart review and an in-person or telephone interview of the parent or caregiver of each patient. Results Twenty-eight (65%) of 43 patients fulfilled the criteria for atopic dermatitis. Thirty-five (81%) of 43 patients reported a newborn rash. Eight (19%) of 43 were born with the rash; 23 (53%) of 43 had acquired the rash within 7 days; 32 (74%) of 43 within 14 days; 34 (79%) of 43 within 30 days; and 35 (81%) of 43 had the rash within 35 days of birth. Conclusions The dermatitis in HIES resembles classic atopic dermatitis but may have distinctive features. A newborn rash is almost always a presenting sign of HIES. After the newborn period, skin findings include retroauricular fissures, external otitis, infected dermatitis of the axillae and groin, folliculitis of the upper back and shoulders, cutaneous abscesses, mucocutaneous candidiasis, and in some patients pitted scarring of the face.
Atopic dermatitis and impaired neutrophil chemotaxis in Job's syndrome. Paslin D, Norman ME.	Arch Dermatol 1977 Jun;113(6):801-5 Abstract quote A 22-year-old white woman with Job's syndrome was found to have atopic dermatitis and impaired neutrophil chemotaxis in vitro. Major clinical features of Job's syndrome included large, "cold" and recurrent staphylococcal abscesses, and intermittent bacterial and yeast infections. Evidence for atopic disease included infantile eczema progressing to flexural dermatitis, a family history of atopy, positive immediate hypersensitivity skin tests, and hyperimmunoglobulinemia E. Defective erythema responses to histamine, methyl niacinate, and methacholine (Mecholyl) chloride may explain the lack of redness, heat, or pain signalling the development of abscesses (hence the term "cold"). Impaired chemotaxis was probably due to an intrinsic neutrophil defect since patient's serum generated normal amounts of chemotactic factors and did not contain an inhibitor of neutrophil chemotaxis. A delay in neutrophil exudation in vivo may explain the abscess formations and the atopic diathesis may explain the absence of clinical signs of inflammation that have been described in this and other patients with Job's syndrome.
HERPES SIMPLEX INFECTION
Herpes simplex virus infection in a hyper-IgE patient: appearance of unusual mass lesions. Hershko K, Hershko AY, Leibovici V, Meir K, Ingber A. Department of Dermatology, Hadassah University Hospital, Jerusalem, Israel.	Acta Derm Venereol. 2002;82(3):204-5. Abstract quote A 7-year-old girl presented with large soft masses rising from the nostril and from behind the ear. She had previously been diagnosed as suffering from hyper-IgE syndrome. The presence of herpes simplex virus infection within these lesions was confirmed by biopsy and immunohistochemical studies. The mass lesions did not respond to antibacterial therapy with cefazolin, but improved promptly under antiviral therapy with acyclovir. Immunological studies revealed a mild decrease in the CD4 cell population. Based on our results and on the relevant literature we propose an immunological mechanism for this unique manifestation of herpes simplex virus infection in hyper-IgE syndrome.
HIV INFECTION
Hyper-IgE and human immunodeficiency virus infection. Lin RY, Smith JK Jr. Department of Medicine, Metropolitan Hospital, NYMC, NY.	Ann Allergy 1988 Oct;61(4):269-72 Abstract quote A 39-year-old black male who is an intravenous drug abuser developed certain clinical manifestations that were consistent with the hyper-IgE syndrome. These included an extremely elevated IgE (greater than 2000 IU/mL), extensive eczematoid dermatitis, and recurrent soft tissue infections. He had no history of atopic disease as a child. Immunophenotypic analysis of peripheral blood mononuclear cells showed a significant decrease in helper (CD 4) cells with a normal concentration of suppressor (CD 8) cells. Human immunodeficiency virus (HIV) antibody was detected in his serum. Previous studies of patients with atopic dermatitis as well as of patients with the hyper-IgE syndrome characteristically show decreases in total suppressor lymphocyte concentrations in peripheral blood. These results led some investigators to postulate that high IgE concentrations in patients with atopic dermatitis result from defective IgE specific suppression. More recent evidence suggests that helper cell function may be the more critical impairment in these disorders. The development of a hyper-IgE syndrome in this setting of T-helper cell viral affliction lends further support to the hypothesis that helper lymphocyte defects may have a key role in the development of atopic dermatitis and the hyper-IgE syndrome.
OSTEOCHONDRITIS DISSECANS
Osteochondritis dissecans in a patient with hyperimmunoglobulin E syndrome. Kilic SS, Sanal O, Tezcan I, Ersoy F. Department of Pediatrics, Uludag University Faculty of Medicine, Bursa, Turkey.	Turk J Pediatr. 2002 Oct-Dec;44(4):357-9. Abstract quote Hyperimmunoglobulin E syndrome (hyper-IgE) is a rare immunodeficiency disease associated with recurrent pyogenic infections, chronic eczematoid dermatitis and osteopenia. We present here a 13-year-old girl with hyperimmunoglobulin E syndrome, who developed osteochondritis dissecans (OCD) of the lateral femoral condyle, which is rare. Osteopenia, which is frequently associated with hyper IgE, may predispose the patient to the development of OCD.
PREGNANCY
Hyperimmunoglobulinemia E and pregnancy: a case report. Lindenbaum C, Chatwani A, Oyer R, Fitzgerald J. Department of Obstetrics and Gynecology, Temple University Hospital, Philadelphia, PA 19140.	Am J Obstet Gynecol 1987 Nov;157(5):1273-4 Abstract quote Hyperimmunoglobulinemia E is characterized by recurrent bacterial sinopulmonary and skin infections from birth or early childhood, with IgE levels at least 10 times greater than the upper limits of normal. The following case describes a young black woman with hyperimmunoglobulinemia E syndrome who had an uneventful pregnancy and delivery. The infant has been diagnosed as suffering from hyperimmunoglobulinemia E syndrome as well.

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Hyperimmunoglobulinemia E syndrome: radiographic observations. Merten DF, Buckley RH, Pratt PC, Effmann EL, Grossman H.	Radiology 1979 Jul;132(1):71-8 Abstract quote Susceptibility to recurrent staphylococcal cutaneous and respiratory infections beginning in infancy associated with extreme hyperimmunoglobulinemia E is a recently described primary immunodeficiency syndrome. Other clinical features include depressed cellular immunity and deficient antibody formation. Recurrent pneumonia and cyst formation with variable persistence and expansion characterized the radiographic couse in 11 patients. Five cysts resolved with continuous antistaphylococcal therapy; 2 were resected without recurrence; and 4 persisted after surgery and/or antibiotics (2--8 years). The cysts had dense, necrotic surfaces with fibrous walls, eosinophilic and other inflammatory cell infiltrates, and frequent, persistent, bronchial connections. Sinusitis (9/9) and mastoiditis (3/4) were also observed radiographically.
LABORATORY MARKERS
LEUKOCYTE CHEMOTAXIS
Severe staphylococcal disease associated with allergic manifestations, hyperimmunoglobulinemia E, and defective neutrophil chemotaxis. Hill HR, Estensen RD, Hogan NA, Quie PG.	J Lab Clin Med 1976 Nov;88(5):796-806 Abstract quote Neutrophil granulocyte function was determined in three patients with systemic staphylococcal infection, clinical manifestations of generalized allergic disease, and hyperimmunoglobulinemia E. Each of the patients had urticarial skin rashes before or at the time of development of staphylococcal suppurative lymphadenitis, pneumonia, or sepsis. Neutrophil chemotaxis, random migration, phagocytosis, and bactericidal capacity were assessed to determine if an abnormality in these functions might have contributed to the development of severe staphylococcal infections. Each of the three patients with generalized urticaria was found to have a marked defect in neutrophil chemotaxis. The mean chemotactic index of the patients was 12 +/- 4, whereas that of 20 controls was 72 +/- 11. Neutrophil random migration, phagocytosis, and bactericidal capacity were normal in each patient. The serum or plasma of the patients did not inhibit chemotaxis of control neutrophils and did not contain an increased concentration of the chemotactic-factor inactivator found in normal serum. Treatment of the neutrophils of these three patients with the competitive histamine H2 receptor blocking agent, burimamide, produced a significant increase in chemotactic responsiveness. These studies suggest the possibility of pharmacologic modification of neutrophil granulocyte function.
A hyperimmunoglobulin E syndrome with normal chemotaxis in vitro and defective leukotaxis in vivo. Weston WL, Humbert JR, August CS, Harnett J, Mass MF, Dean PB, Hagen IM.	J Allergy Clin Immunol 1977 Feb;59(2):115-9 Abstract quote A 26-yr-old male with a lifelong history of atopic dermatitis and recurrent severe staphylococcal abscesses was found to have hyperimmunoglobulinemia E. Evaluation of both the humoral and cellular aspects of chemotaxis in vitro showed both neutrophils and monocytes to be normal. However, quantitative neutrophil migration in vivo was significantly suppressed using the patient's own serum as the attractant. This defective migration in vivo was partially corrected by serum from normal donors as the attractant and also partially corrected following plasma infusion in this patient. Evaluation of quantitative leukocyte migration in vivo may be most useful in patients suspected of defects of leukocyte mobility.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Prognosis
Treatment
Commonly Used Terms
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EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Buckley syndrome Job's syndrome
INCIDENCE	Rare
GEOGRAPHY
WAORANI INDIANS
Hyperimmunoglobulinemia E in the Waorani, an isolated Amerindian population. Kaplan JE, Larrick JW, Yost JA.	Am J Trop Med Hyg 1980 Sep;29(5):1012-7 Abstract quote The Waorani Indians of Eastern Ecuador have the highest blood levels of immunoglobulin E that have been recorded in a human population. Using a radial immunodiffusion technique for IgE determination, we found the mean plasma IgE concentration for the entire sample (n = 227) to be 11,975 International Units per milliliter (normal: 5--500 IU/ml). The reason for the elevated IgE concentrations is unclear, although genetic factors and a high prevalence of parasitic infection may be involved. Atopic disease is rare among the Waorani as determined by medical history, physical examination, and immediate hypersensitivity skin tests. Our data are consistent with the association between hyperimmunoglobulinemia E and low prevalence of atopic disease in tropical populations. The significance of the findings with regard to the control of allergic disorders is discussed.

PATHOGENESIS	CHARACTERIZATION
CYTOKINES
Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome. Borges WG, Augustine NH, Hill HR. Departments of Pathology, Pediatrics, and Medicine, University of Utah School of Medicine, and the ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84132, USA.	J Pediatr 2000 Feb;136(2):176-80 Abstract quote OBJECTIVE: Patients with the hyperimmunoglobulinemia E (hyper-IgE) syndrome are reported to have defective production of interferon gamma (IFN-gamma). Because IFN-gamma is a major activator of polymorphonuclear leukocytes (PMNs), this could result in defective PMN chemotaxis and markedly elevated IgE levels because of the unopposed action of interleukin (IL)-4. IL-12, an important enhancer of IFN-gamma production, also suppresses IgE production. This study assessed the IL-12/IFN-gamma pathway in patients with hyper-IgE syndrome. METHODS: Production of IL-12 and IFN-gamma by mononuclear cells from 10 patients with hyper-IgE syndrome in response to a number of stimuli was determined, as well as the effect of IL-12 on IFN-gamma release and cell proliferation. RESULTS: IL-12 and IFN-gamma production by the patients' cells was similar to that of control subjects independent of the stimulus used, except for Staphylococcus aureus, with which cells of patients with hyper-IgE syndrome released markedly less IFN-gamma (19.8%; P <.002). The ability of recombinant IL-12 to enhance IFN-gamma release from patients' cells in response to all stimuli was, however, significantly lower than with control cells (12% to 51%; P <.03). CONCLUSION: The lymphocytes of patients with hyper-IgE syndrome have an impaired response to IL-12, resulting in decreased IFN-gamma production, which may be of key importance in the pathogenesis of the immune abnormalities of hyper-IgE syndrome.
IgE RECEPTOR
IgE Fc receptor positive T, B and NK cells in patients with the hyper-IgE syndrome. Spiegelberg HL, Thompson LF, McNeil D, Buckley RH.	Int Arch Allergy Appl Immunol 1985;77(1-2):277-9 Abstract quote Patients with the hyper-IgE syndrome have greatly elevated percentages of IgE Fc receptor (Fc epsilon R)-positive B cells, but they have less than 0.1% Fc epsilon R+ T cells (T epsilon cells) and few, if any, Fc epsilon R+ natural killer cells. They also have markedly decreased numbers of IgG receptor positive (Fc gamma R+) T cells (T gamma cells). Patients with the hyper-IgE syndrome resemble in this respect patients with severe atopic dermatitis. Since a portion of T epsilon and T gamma cells of mildly atopic patients react with monoclonal antibody OKT8, they may have a suppressor function. However, whether the low number of T epsilon cells is responsible for the high IgE serum level in hyper-IgE syndrome and atopic dermatitis patients remains to be demonstrated. Attempts to obtain a reliable assay for human IgE synthesis in vitro to investigate the function of Fc epsilon R-positive lymphocytes proved to be difficult. Even isolated B cells from atopic donors seldom produced more than twice the quantity of IgE released from cells incubated in the presence of the protein synthesis inhibitor cycloheximide.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
TREATMENT
INTRAVENOUS IMMUNOGLOBULIN
Moderate-dose intravenous immunoglobulin treatment of Job's syndrome. Case report. Bilora F, Petrobelli F, Boccioletti V, Pomerri F. Department of Surgery and Medicine, Padua University.	Minerva Med 2000 May-Jun;91(5-6):113-6 Abstract quote Job's syndrome (or hyperimmunoglobulinemia E syndrome) is a rare genetic disease characterized by skin eczema, pyogenic "cold" abscesses, sinopulmonary recidivous infections and high IgE plasma concentrations. Job's syndrome treatment is not satisfactory and cases studied are still limited. To describe the effects of IVIG therapy in a 37-year-old woman with hyper IgE syndrome and pneumonia. We measured IgE serum by immuno-fluorometric test and neutrophil chemotaxis by migration in a Boyden chamber before and after IVIG therapy. A moderate dose of IVIG resolved the clinical-radiological signs of the S. aureus bronchopneumonia and improved cytologic and biohumoral parameters. Intravenous immunoglobulins represent a useful treatment for acute pneumonia in Job's syndrome.