eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Hyperimmunoglobulinemia E (Job) Syndrome

Author: Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Jun 8, 2009

Introduction

Background

Hyperimmunoglobulin E syndrome (HIES) was first described as Job syndrome in 1966, when 2 patients were reported with eczematous dermatitis, recurrent staphylococcal boils, hyperextensible joints, and distinctive coarse faces.

Father and daughter with autosomal dominant (AD) ...

Father and daughter with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.

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Father and daughter with autosomal dominant (AD) ...

Father and daughter with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.



Mother and son with autosomal dominant (AD) hyper...

Mother and son with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the mother's distinctive facies. She had a history of multiple deep-seated abscesses that took months to heal after incision and drainage.

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Mother and son with autosomal dominant (AD) hyper...

Mother and son with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the mother's distinctive facies. She had a history of multiple deep-seated abscesses that took months to heal after incision and drainage.


Buckley et al expanded the clinical picture in 1972 and reported the association with elevated immunoglobulin E (IgE) in patients with hyperimmunoglobulin E syndrome.1 Hyperimmunoglobulin E syndrome is now recognized as a primary immunodeficiency characterized by recurrent skin abscesses, recurrent cystic lung disease, and elevated serum IgE levels. Hyperimmunoglobulin E syndrome was initially believed to have an autosomal dominant (AD) inheritance pattern, but sporadic cases of hyperimmunoglobulin E syndrome and cases with autosomal recessive (AR) inheritance have been described.

Mutations of signal transducer and activator of transcription 3 (STAT3) gene were recently shown to cause the AD hyperimmunoglobulin E syndrome by 2 groups independently.2,3 In addition tyrosine kinase 2 deficiency (tyk2) deficiency was reported in one patient with hyperimmunoglobulin E syndrome.4,5  A fair numbers of patients with AD hyperimmunoglobulin E syndrome have STAT3 mutations; however, some patients have AD hyperimmunoglobulin E syndrome–like disease without STAT3 mutations.

In AD hyperimmunoglobulin E syndrome and sporadic cases, hyperimmunoglobulin E syndrome manifested as a disease that affects multiple organ systems, including the skeleton, connective tissue, and dentition systems. AD hyperimmunoglobulin E syndrome is inherited as a single-locus trait with various expressivity in some families. In contrast, patients with AR hyperimmunoglobulin E syndrome lack skeletal or dental involvement and do not develop cystic lung disease. However, patients with AR hyperimmunoglobulin E syndrome are susceptible to viral infection characterized by severe Molluscum contagiosum and may develop severe neurological complications for unknown reasons.6

The immunologic features of hyperimmunoglobulin E syndrome are characterized by recurrent skin abscesses, cystic lung infections (primarily Staphylococcus aureus and Candida species [chronic mucocutaneous candidiasis]), eczematous dermatitis, eosinophilia, and elevated IgE levels. Nonimmunologic features of AD hyperimmunoglobulin E syndrome include multiple bone fractures and other skeletal abnormalities, coarse facial features, joint hyperextensibility, and retained primary dentition. AR hyperimmunoglobulin E syndrome is distinguished from AD hyperimmunoglobulin E syndrome by increased susceptibility to viral infection as characterized by severe M contagiosum, lack of pneumatocele formation, and normal dentition and skeleton.6 Sporadic cases of hyperimmunoglobulin E syndrome were reported to have similar clinical features as those observed in AD hyperimmunoglobulin E syndrome.7

Pathophysiology

Because recurrent skin and lung infections and marked elevation of IgE levels are the hallmarks of hyperimmunoglobulin E syndrome, investigations have focused on defining a basic immune defect that leads to both recurrent infection with certain organisms (S aureus and Candida species) and elevated IgE synthesis in hyperimmunoglobulin E syndrome. This line of research led to the findings of an imbalance of TH 1 and TH 2 responses, low interferon (IFN)-γ and relatively high interleukin (IL)-4 production and expression, defects in IFN-γ and IL-12 pathway, underexpression of certain chemokines and adhesion molecules, and reduced expression of transforming growth factor β (TGF-β) and IFN-γ messenger RNA (mRNA) in circulating activated (DR+) T cells.8,9

These findings may partly explain the marked elevation of IgE levels and recurrent infection in certain patients with hyperimmunoglobulin E syndrome. However, serum IgE levels do not positively or negatively correlate with production or expression of these cytokines. IgE levels may also be associated with epigenetic regulation in patients with hyperimmunoglobulin E syndrome. Some infants with hyperimmunoglobulin E syndrome may not demonstrate elevated IgE levels from early infancy, whereas some older patients may demonstrate sudden decline in IgE levels without clinical improvement, as experienced by the author and other clinical immunologists.

More importantly, the above-referred immune abnormalities do not explain the facial, skeletal, joint, and dental defects in AD hyperimmunoglobulin E syndrome. Humans or mice who lack IFN-γ production or the IFN-γ receptor expression do not have facial or bony abnormalities. Patients with receptor defects of IFN-γ or IL-12 have disseminated atypical mycobacterial infections with incomplete granuloma formation and do not exhibit clinical features of hyperimmunoglobulin E syndrome.10  Likewise, transgenic mice that overexpress IL-4 do not have the nonimmunologic features of hyperimmunoglobulin E syndrome.

Recently, several researchers also explored possible defects in toll-like receptor (TLR)–mediated signaling in patients with hyperimmunoglobulin E syndrome. However, the results do not indicate the defects in TLR responses or signaling, although a decrease in IFN-γ production and a shift to predominant TH 2 responses were observed in these patients and were consistent with previous reports.11,12

In addition to immune defects that affect IgE synthesis, defects of cell-mediated immunity have also been reported, consistent with decreased TH 1 responses. These include decreased or absent delayed-type hypersensitivity in some patients with hyperimmunoglobulin E syndrome and decreased lymphoproliferative responses to S aureus, Candida species, and tetanus antigens. Decreased numbers and functions of CD8+ were also reported in some patients with hyperimmunoglobulin E syndrome, but these findings vary in each patient. A decrease in T cells that express CD45RO, the marker for memory T cells, was also reported by other investigators. In one patient with hyperimmunoglobulin E syndrome, the presence of the IL-4-producing g/d T-cell clone was reported.13

Recent identification of STAT3 mutations as a cause of AD hyperimmunoglobulin E syndrome is very helpful in understanding the clinical features of hyperimmunoglobulin E syndrome. The initial report of the STAT3 mutation in patients with hyperimmunoglobulin E syndrome reported dominant-negative mutations in the DNA binding domain of STAT3.2 A subsequent study reported 2 hot spots of mutations: DNA binding and SH2 domains.3 Other mutations of STAT3 in hyperimmunoglobulin E syndrome have also been reported.14

STAT3 is implicated in the signal transduction of multiple cytokine families including the IL-2/common g chain family (IL-2, IL-7, IL-9, IL-15, IL-21), the IL-6/gp130 family (IL-6, IL-11, IL-27, IL-31, ciliary neurotropic factor, oncostatin M, leukemia inhibitory factor), IFNs, and the IL-10 family (IL-10, IL-19, IL-20, IL-22, IL-24, IL-26). STAT3 is also implicated in signaling pathways of IL-12, IL-23, Flt3 ligand, macrophage-colony stimulating factor (M-CSF), granulocyte-colony stimulating factor (G-CSF), leptin, and growth hormone.15  STAT3 mutations have a key role in the signaling pathways of multiple cytokines and affect multiple organ systems, as revealed in humans and STAT3 knockout (KO) mice. Findings include the following:

  • CD4+ T cells: Th17 deficiency and impaired IL-10 production in this lineage are the result of impaired STAT3 signaling.16  Th17 cells are a recently identified Th-cell subset characterized by the production of IL-17A, IL-17F, IL-21, IL-22, IL-26, and CCL20. They are now known to play a major immune defense against extracellular pathogens such as mycobacterium and fungi. Patients with AD hyperimmunoglobulin E syndrome are shown to have impaired Th17 cell differentiation.17,14  This is attributed to impaired signaling of IL-6, a key differentiation factor for Th17 cells. Impaired IL-10 production is attributed to the fact that STAT3 deficiency abrogates the ability of IL-6 and IL-27 to induce production of IL-10 by CD4+ T cells.
  • B cells: In STAT3 KO mice, mice are found to have impaired antibody (Ab) production against T-dependent antigens (Ags). Patients with AD hyperimmunoglobulin E syndrome are also reported to have impaired functional Ab formation. However, reduced isotype-switched memory B cell numbers in patients with AD hyperimmunoglobulin E syndrome are not associated with their functional Ab production or infection history.18
  • Myeloid cells: Patients with AD hyperimmunoglobulin E syndrome have up-regulated proinflammatory cytokine production. One of the counter-regulatory measures for proinflammatory cytokines is autocrine production of IL-10 by myeloid lineage cells such as marcophages and monocytes. Because IL-10 receptor signaling is mediated by STAT3, this IL-10 mediated suppression is lost in STAT3 KO mice as well as in patients with AD hyperimmunoglobulin E syndrome who have STAT3 mutations. This defect likely explains hyperinflammatory features of AD hyperimmunoglobulin E syndrome. Impaired signaling via Flt3 ligand also affects dendritic cell (DC) development and results in lower numbers of DCs in STAT3 KO mice.15
  • Osteoclasts: Cytokines of IL-6 family have roles in bone homeostasis and their signaling pathways mediates via STAT3. Thus, impaired STAT signaling results in increased bone resorption by osteoclasts. This may explain clinical features of AD hyperimmunoglobulin E syndrome that affect the skeletal system.

Frequency

United States

Frequency is undetermined. Published reports are from the United States and Europe. A recent population-based study concluded that the incidence of all primary immunodeficiencies markedly increased between 1976-2006.19

International

Frequency is undetermined.

Mortality/Morbidity

Although the oldest reported patient was aged approximately 60 years, deaths in the second and third decades of life due to severe pulmonary disease and infection of pneumatoceles with Aspergillus species, Pseudomonas aeroginosa, or other organisms have been reported in patients with AD hyperimmunoglobulin E syndrome.20 Infections are the major cause of morbidity; approximately 80% of patients have pneumatoceles secondary to pneumonia, and a similar percentage have chronic mucocutaneous and ungual candidiasis. Morbidity includes bone fractures with minor injury in approximately 60% of patients with AD hyperimmunoglobulin E syndrome.

In patients with AR hyperimmunoglobulin E syndrome, morbidity and mortality are closely associated with CNS complications and autoimmunity. Patients with AR hyperimmunoglobulin E syndrome seem to have frequent complications with varicella-zoster and herpes simplex viruses at a younger age. As described previously, patients with AR hyperimmunoglobulin E syndrome also frequently develop severe chronic refractory M contagiosum infections.

Race

Hyperimmunoglobulin E syndrome has been reported in all racial groups in the United States, but exact incidence cannot be determined because of the rarity of the disease. The presence of disease in multiple racial groups is significant because it suggests that multiple different mutations in the same genes are present.

Sex

Prevalence is equal in males and females. AD hyperimmunoglobulin E syndrome is inherited with variable penetrance.

Age

Patients with AD hyperimmunoglobulin E syndrome range in age from 0-60 years. Because not all patients have the same spectrum of infections, facial features, and skeletal anomalies, some patients are not identified until later in life when more chronic illness develops. Most patients with AR hyperimmunoglobulin E syndrome are diagnosed when younger than 20 years because of characteristic clinical features (eg, skin abscesses, recurrent pneumonia, markedly elevated IgE levels).

Clinical

History

Infants in families with hyperimmunoglobulin E syndrome (HIES) often exhibit severe eczema complicated by mucocutaneous candidiasis involving the mouth and diaper areas in the first few weeks of life. Lichenification quickly follows; then recurrent otitis media soon develops. Wheezing is not common; a persistent cough beginning in infancy is common. Chronic, disfiguring M contagiosum infection has also been reported in patients with autosomal recessive (AR) hyperimmunoglobulin E syndrome but not in those with autosomal dominant (AD) hyperimmunoglobulin E syndrome.

Recurrent or chronic otitis media and sinusitis persist into adulthood. Although surgical intervention has been recommended in these patients, in the author's experience, sinus surgery seldom has favorable outcomes, and persistent otorrhagia may result after the surgery.

  • Food and respiratory allergens can be identified using routine allergy testing; however, avoiding known allergens has minimal influence on patient's dermatitis or other atopic features of hyperimmunoglobulin E syndrome.
  • In patients with AD hyperimmunoglobulin E syndrome, fractures can result from minimal trauma (pathological fractures). Long bones, ribs, vertebrae, and pelvic bones are those most commonly broken.
  • Pneumatoceles often develop occultly following pneumonia in people with AD hyperimmunoglobulin E syndrome. Chronic coughing with purulent sputum accompanies pneumatocele formation. In AR hyperimmunoglobulin E syndrome, pneumatoceles rarely develop.
  • Isolated malignancies reported in people with hyperimmunoglobulin E syndrome include lymphoma and squamous cell carcinoma.
  • In a retrospective study, vasculitis was reported in 3 of 30 patients. Recurrent autoimmune hemolytic anemia was also reported in 2 of 13 patients with AR hyperimmunoglobulin E syndrome.
  • In patients with AR hyperimmunoglobulin E syndrome, neurological symptoms are frequently seen, and these appear to be highly associated with vascular abnormalities including stenosis, occlusion, and aneurysm formation.
  • Coronary artery aneurysms were reported in 2 patients with AD hyperimmunoglobulin E syndrome who were in their fifth decade of life. In contrast, fatal aneurysmal dilatation of the thoracic aorta has been reported in 2 adolescents with AR hyperimmunoglobulin E syndrome.
  • Family members without hyperimmunoglobulin E syndrome are not reported to have increased incidences of isolated fractures, facial anomalies, vasculitis, or malignancy. They also have normal immunoglobulin E (IgE) levels.
  • When atopic predisposition is significant in the family, patients with hyperimmunoglobulin E syndrome seem to have more severe skin and pulmonary symptoms.
  • A patient with tyk2 deficiency exhibits more severe clinical features very vulnerable to intracellular bacteria as well as extracellular bacteria. This is attributed to impaired signaling mediated by interleukin (IL)-6, IL-10, IL-12, and IL-23.4

Physical

Facial abnormalities and eczema somewhat varies at different ages. Infants and toddlers with AR hyperimmunoglobulin E syndrome often do not demonstrate the distinctive faces of older patients. By mid childhood, however, most patients with AD hyperimmunoglobulin E syndrome have coarse faces, a prominent forehead, a broad nasal bridge, and a bulbous nose. Midline facial anomalies such as cleft lip and palatal abnormalities may be present. Craniosynostosis has been reported in a few patients. Such skeletal abnormalities do not appear to be present in patients with AR hyperimmunoglobulin E syndrome.

  • Eczematous dermatitis and lichenification affect the face, trunk, and extremities in a distribution similar to that found in people without hyperimmunoglobulin E syndrome who have atopic dermatitis. Dermatitis is pruritic, leading to excoriation. It differs from typical eczema in that the weeping, superinfected severe eczematous skin lesions are less frequent; patients with hyperimmunoglobulin E syndrome instead develop boils, deep-seated cold abscesses, and even pyomyositis. Multiple guidelines have been established for the diagnosis and management of atopic dermatitis.21,22
  • In patients with AD hyperimmunoglobulin E syndrome, multiple fractures may lead to asymmetry in the extremities or the chest wall. Scoliosis developing during adolescence and vertebral abnormalities cause spinal deformity. One recent study reported hyperextensible joints in approximately 70% of patients. Dental abnormalities are also frequently seen in people with AD hyperimmunoglobulin E syndrome. Some patients with AD hyperimmunoglobulin E syndrome reportedly fail to shed their primary teeth. They may retain these teeth even as permanent teeth erupt.
  • Chronic sinusitis, chronic bronchitis, and lung abscesses (for patients with AD hyperimmunoglobulin E syndrome) are common sinopulmonary findings. A purulent sputum-producing cough is common in patients who develop pneumatoceles, although some individuals have a dry cough associated with sinopulmonary infection. Wheezing is highly unusual in people with hyperimmunoglobulin E syndrome and is more suggestive of atopy asthma with elevated IgE levels. The common manifestation in patients with AD hyperimmunoglobulin E syndrome includes a chronic cough and pneumatoceles in the second decade of life.
  • Because AD hyperimmunoglobulin E syndrome affects multiple organ systems and because clinical features may change with age, the National Institutes of Health (NIH) developed a scoring system for clinical diagnosis. A clinical point score of more than is reported to be highly likely to have AD hyperimmunoglobulin E syndrome. Clinical findings included in this scoring system include highest serum IgE level, skin abscesses, pneumonia, parenchymal lung anomalies, retained primary teeth, scoliosis (maximum curvature), fractures with minor trauma, highest eosinophil count, characteristic coarse facial features, midline anomaly, newborn rash, eczema (worst stage), upper respiratory tract infection frequency, candidiasis, other serious infections, fetal infection, hyperextensibility, lymphoma, increased nasal width, and high palate. Scores are corrected with young age.

Causes

  • As detailed in Pathophysiology, recent studies revealed that many cases of AD hyperimmunoglobulin E syndrome are associated with 2 hot spots of STAT3 mutations: DNA binding and SH2 domains.
  • The etiology is unknown in AR hyperimmunoglobulin E syndrome.

More on Hyperimmunoglobulinemia E (Job) Syndrome

Overview: Hyperimmunoglobulinemia E (Job) Syndrome
Differential Diagnoses & Workup: Hyperimmunoglobulinemia E (Job) Syndrome
Treatment & Medication: Hyperimmunoglobulinemia E (Job) Syndrome
Follow-up: Hyperimmunoglobulinemia E (Job) Syndrome
Multimedia: Hyperimmunoglobulinemia E (Job) Syndrome
References
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References

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

  32. 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].

  33. Paganelli R, Scala E, Capobianchi MR, et al. Selective deficiency of interferon-gamma production in the hyper-IgE syndrome. Relationship to in vitro IgE synthesis. Clin Exp Immunol. Apr 1991;84(1):28-33. [Medline].

  34. Seroogy CM, Wara DW, Bluth MH, et al. Cytokine profile of a long-term pediatric HIV survivor with hyper-IgE syndrome and a normal CD4 T-cell count. J Allergy Clin Immunol. Nov 1999;104(5):1045-51. [Medline].

  35. Van der Meer JW, Weemaes CM, van Krieken JH, et al. Critical aneurysmal dilataion of the thoracic aorta in young adolescents with variant hyperimmunoglobulin e syndrome. J Intern Med. 2006;259:615-8. [Medline].

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Further Reading

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Keywords

hyperimmunoglobulin E syndrome, hyper-IgE syndrome, Job syndrome, Job's syndrome, HIE, HIE syndrome, HIES, immunoglobulin E, IgE, dermatitis, eczema, eczematous dermatitis, immunodeficiency disease, Staphylococcal keratoconjunctivitis, pneumatoceles, T-cell abnormality, Staphylococcus aureus, chronic mucocutaneous candidiasis, multiple fractures, skeletal abnormalities, coarse facies, chronic mucocutaneous, ungual candidiasis, lichenification, otitis media, IL-4, IL-6, IL-10, IL-17, Pseudomonas aeruginosa, Aspergillus, interferon γ, autosomal dominant hyperimmunoglobulin E syndrome, autosomal recessive hyperimmunoglobulin E syndrome, AR-HIES, autosomal recessive inheritance, AD-HIES, bone marrow transplantation, BMT, hyperimmunoglobulinemia E syndrome, cystic lung disease, sinusitis, Molluscum contagiosum, lymphoma, squamous cell carcinoma, treatment, diagnosis 

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Contributor Information and Disclosures

Author

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David J Valacer, MD, Consulting Staff, Hoffman La Roche Pharmaceuticals
David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

 
 
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