Job syndrome, initially named after the biblical character Job because of its description that resembles patients suffering from this condition, is more commonly referred to as hyper-immunoglobulin E syndrome, a form of primary immunodeficiency that affects multiple systems [1] [2] [3] [4]. Two forms have been described so far:

• Autosomal dominant - Mutations in the signal transducer and activator of transcription 3 (STAT3) gene, which seems to affect the activity of interleukins 6 and 22 (IL-6 and IL-22, respectively), causing changes in Th17 cell function [5], is the primary cause of this syndrome [1] [2] [5]. As a result of these immunological deficits, recurrent bacterial infections of the skin and the lungs are one of the main clinical manifestations [1]. Staphylococcus aureus is the causative agent of furuncles (or boils), which are the hallmark of Job syndrome, whereas a neonatal onset of pustules and eczema (primarily affecting the face and scalp) is an equally important cutaneous sign [1] [4]. Mucocutaneous infections by candida albicans, in the form of oral thrush, onychomycosis, or vaginal infections, are also reported in a significant number of cases [1] [2]. Conversely, streptococcus pneumoniae and haemophilus influenza are main pathogens implicated in the development of recurrent pyogenic pneumonia (presenting with a cough and sputum production), another key feature of Job syndrome [1]. In addition to infections, skeletal changes (scoliosis, osteopenia, increased rate of pelvic and rib bone fractures, as well as degenerative joint disease), dental abnormalities (retention of primary teeth is common) and facial asymmetry with deep-set eyes and a prominent nose comprise the symptomatology of Job syndrome [1] [2] [6].
• Autosomal recessive - The absence of skeletal and connective tissue symptoms, but with severe cutaneous involvement (particularly eczema) is the main distinguishing feature of autosomal recessive Job syndrome [5]. In addition to the mentioned pathogens responsible for lung infections seen in autosomal dominant forms, pseudomonas aeruginosa, proteus mirabilis, but also cryptococcus, pneumocystis jirovecii, adenovirus, and respiratory syncytial virus are important causative agents of pneumonia that may lead to life-threatening complications and sepsis [1] [5].

• Recurrent Infection

  Syndromes[accessedResource: MSH:D007589][accessDate: 05-04-2011], Primary immunodeficiency syndrome characterized by recurrent infections and hyperimmunoglobulinemia E. [ebi.ac.uk]

  HIES is characterized by eczema, recurrent infections of the skin and lungs, and elevated levels of serum IgE [3]. [ajronline.org]

  Hyper-IgE recurrent infection syndrome is a primary immunodeficiency disorder characterized by chronic eczema, recurrent staphylococcal infections, increased serum IgE, and eosinophilia. [humpath.com]

  infection syndrome ( HIES ) is a primary immunodeficiency characterized by recurrent respiratory and skin infections, eczema, pneumatocele-forming pneumonias, elevated serum IgE level, and eosinophilia. [invitae.com]

  Other Names for This Condition AD-HIES autosomal dominant HIES autosomal dominant hyper-IgE recurrent infection syndrome autosomal dominant hyperimmunoglobulin E recurrent infection syndrome autosomal dominant Job syndrome Buckley syndrome Job syndrome [encyclopedia.pub]

• Candidiasis

  Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. [ncbi.nlm.nih.gov]

  Mucocutaneous candidiasis is common. A characteristic facial appearance typically develops in adolescence. Skeletal abnormalities include osteopenia, minimal trauma fractures, and scoliosis. [humpath.com]

  Additionally, patients can develop chronic mucocutaneous candidiasis involving the oral mucosa/nails and rare cases of Pneumocistis jirovecii infection have been reported. 3. [immunodeficiencysearch.com]

• Failure to Thrive

  […] to thrive and recurrent bacterial, viral, fungal, and protozoal infections Diagnosis STAT3 genetic testing to confirm diagnosis Treatment First-line antibiotics indication treat infections as they arise skin care for eczematoid dermatitis modalities [step2.medbullets.com]

  Other features of Netherton syndrome include environmental and food allergies, enteropathy, and failure to thrive. [invitae.com]

  These patients also present with fragile hair, ichthyosis linearis circumflexa, and failure to thrive (Sprecher et al., 2001. PMID: 11511292). [preventiongenetics.com]

  […] to thrive: A case report Melissa M. [e-ijd.org]

  Similar to graft vs host disease, generalized exudative erythroderma with desquamation, lymphadenopathy and hepatosplenomegaly are seen along with severe respiratory tract infections, intractable diarrhea and failure to thrive (FTT). [medcraveonline.com]

• Prognathism

  Coarse atypical facies were noticed with a prominent forehead, deep set eyes, broad nasal bridge, wide fleshy nasal tip and mild prognathism as shown in Figure -1a and b. Oral examination showed a high arched palate with a normal dentition. [jpma.org.pk]

  These include facial asymmetry, a prominent forehead, deep-set eyes, a broad nasal bridge, a wide, fleshy nasal tip, and mild prognathism. Additionally, facial skin is rough with prominent pores. [en.wikipedia.org]

  Etiology germline mutations of STAT3 (MIM.102582) in hyper-IgE syndrome (MIM.147060) (autosomal dominant hyper-IgE recurrent infection syndrome / Job-Buckley syndrome) Clinical synopsis coarse facies asymmetric face prominent forehead mild prognathism [humpath.com]

  A total of 97% of patients have serum IgE > 2,000 ng/ml, and 83% of HIES patients exhibit typical facial features that include a prominent forehead, facial asymmetry, sunken eyes, broad nasal ridge and fleshy nose, prognathism, and craniosynostosis. [medicaljournals.se]

  Characteristic facial appearance (facial asymmetry, prominent forehead, sunken eyes, broad nasal ridge, fleshy nose, prognathism, craniosynostosis), pneumatoceles, skeletal abnormalities (scoliosis and fractures) and delayed shedding of primary teeth [clinmedjournals.org]

• Fracture

  Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. Markers of bone metabolism did not correlate with minimal trauma fractures or BMD. [ncbi.nlm.nih.gov]

  "Bone density and fractures in autosomal dominant hyper IgE syndrome". J Clin Immunol. 34 (2): 260–4. doi:10.1007/s10875-013-9982-2. PMC 4484798. PMID 24402620. ↑ Kimata H (1995). [wikidoc.org]

• Osteoporosis

  Osteopenia or osteoporosis was found in 79% of children and adults. Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. [ncbi.nlm.nih.gov]

  Osteopenia or osteoporosis was found in 79 % of children and adults. Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. [link.springer.com]

  The first sign of the disease is pustules and eczematoid rashes of the face and scalp. skeletal manifestations scoliosis minimal trauma fractures due to osteoporosis hyperextensibility of the joints delayed exfoliation of primary teeth, then normal permanent [radiopaedia.org]

• Hyperextensible Joints

  Nonimmunologic manifestations of HIES include a characteristic face, pathologic dentition, scoliosis, bone alterations, hyperextensible joints, and vascular abnormalities. [ncbi.nlm.nih.gov]

  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). [scienceopen.com]

  Hyperextensible joints including scoliosis and talipes cavus [Figure 1c] were also seen. There was no abnormality of the hair or nails. [journals.lww.com]

  Hyperextensible joints including scoliosis and talipes cavus [Figure 1] c were also seen. There was no abnormality of the hair or nails. [idoj.in]

  Eczema, mucocutaneous candidiasis, retention of the primary teeth, coarse facial features, osteopenia, hyperextensible joints and increased risk of malignancy are also common. [medcraveonline.com]

• Eczema

  AR-HIES is due to null mutation in tyrosine kinase 2 gene causing defect in innate and adaptive immunity and susceptibility eczemas, skin and pulmonary infection with increased serum IgE levels. [ijdvl.com]

  Hyper-IgE syndrome (HIES) is a rare group of primary immunodeficiency characterised by recurrent infections, eczema, and elevated serum levels of IgE. [e-ijd.org]

  AR-HIES are rare combined immunodeficiencies where susceptibilities to viral infection, atopic eczema have been described. [ukm.my]

  A common mnemonic used to remember the symptoms is FATED: coarse or leonine facies, cold staph abscesses, retained primary teeth, increased IgE, and dermatologic problems [eczema]. [en.wikipedia.org]

  Skin Care - Eczema should be treated with emollients and topical anti-inflammatory medications. Superinfection of eczema requires treatment with systemic antibiotics. [immunodeficiencysearch.com]

• Dermatitis

  CONCLUSION: When associated with serum IgE levels 10 times the age-appropriate level, a neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis that differs from classic atopic dermatitis is highly suggestive of AD-HIES [ncbi.nlm.nih.gov]

  Dermatitis is treated with skin hydration, emollient creams, antihistamines. and, if infections are suspected, antibiotics. Pulmonary infections are treated early and aggressively with antibiotics. [msdmanuals.com]

  Hyper-IgE syndrome is a hereditary combined B- and T-cell immunodeficiency characterized by recurrent staphylococcal abscesses of the skin, sinopulmonary infections, and severe pruritic eosinophilic dermatitis. [merckmanuals.com]

• Eruptions

  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. [thedoctorsdoctor.com]

  Tooth development and the eruption of permanent molars occurred on time, suggesting impaired resorption of primary teeth rather than defective eruption. [nejm.org]

  This "early rash" was distinguished from other neonatal pustular eruptions by crusted papules and pustules, rash intensity, and a continuum with chronic dermatitis. [ncbi.nlm.nih.gov]

  […] of teeth Delayed eruption Delayed teeth eruption Delayed tooth eruption Eruption, delayed Late eruption of teeth Late tooth eruption [ more ] 0000684 Dystrophic fingernails Poor fingernail formation 0008391 Eosinophilia High blood eosinophil count 0001880 [rarediseases.info.nih.gov]

• Skin Rash

  Diseases Targeted: AD-HIES AR-HIES Netherton Syndrome PGM3 Deficiency TYK2 Deficiency Overview: Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by eczema and recurrent skin rash, elevated serum IgE, recurrent staphylococcal [fulgentgenetics.com]

  This can include: Antibiotics to treat infections Cream medicine for skin rash Checking pulmonary (lung) function with spirometry and imaging Some patients may need to take medicine every day to prevent infection Some patients may need to get an IV medicine [cincinnatichildrens.org]

  IgE plays an important role in starting allergic reactions in the body and may be related to some HIES symptoms, such as skin rashes and asthma. Patients also have frequent lung infections, easily broken bones and other symptoms. [clinicaltrials.gov]

  Presentation[edit] It is characterized by recurrent "cold" staphylococcal infections (due to impaired recruitment of neutrophils),[2] unusual eczema-like skin rashes, severe lung infections that result in pneumatoceles (balloon-like lesions that may be [en.wikipedia.org]

  The first symptom of AD-HIES may be a dry, red flaky skin rash (eczema) that develops at birth or early during infancy. Itchiness (pruritis) may also occur. [rarediseases.org]

• Erythema

  There is some pus drainage but no erythema and no warmth. The lesions are cool to the touch. On physical exam, he is noted to have retained primary teeth, eczematous patches on his cheeks, and 2 cold abscesses on his right knee. [step2.medbullets.com]

  […] resorption of primary tooth roots recurrent sinopulmonary infections joint hyperextensibility decreased bone mineral density recurrent fractures eczema, severe recurrent skin abscesses recurrent Staphylococcus aureus infections abscesses are ’cold,’ lacking erythema [humpath.com]

  Recurrent skin infection with S. aureus results in “cold” abscesses lacking the usual features of warmth and erythema, and is a nearly universal feature of HIES. Sinopulmonary infections caused by S. aureus are also common in HIES. [medicaljournals.se]

  Figure 1: Multiple pearly white umbilicated papules over perivulval areas Click here to view Figure 2: Multiple periorbital pearly white papules with surrounding erythema and inflammation Click here to view Figure 3: Multiple, flat-topped, small papules [e-ijd.org]

  Upper gastrointestinal (GI) endoscopy showed two large linear ulcers and whitish exudates in the distal esophagus, pangastric erythema and duodenal erosions. [jpma.org.pk]

• Suggestibility

  The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis. [ncbi.nlm.nih.gov]

  Here, we describe three patients with a characteristic infectious history suggesting HIES but with only moderately elevated serum IgE levels. [lasid.org]

  This patient's blood routine results suggested elevated eosinophils, the serum IgE was more than 3200 IU/ml (≤ 90 IU/ml). [bmcneurol.biomedcentral.com]

• Broad Nasal Bridge

  His facial abnormalities was obvious including a prominent forehead, a broad nasal bridge, deep set eyes, broad outer canthal distance [Figure 1a]. [journals.lww.com]

  His facial abnormalities was obvious including a prominent forehead, a broad nasal bridge, deep set eyes, broad outer canthal distance [Figure 1] a. [idoj.in]

  Hyperextensible joints/recurrent bone fractures, and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance) in early childhood. [wikidoc.org]

  Coarse atypical facies were noticed with a prominent forehead, deep set eyes, broad nasal bridge, wide fleshy nasal tip and mild prognathism as shown in Figure -1a and b. Oral examination showed a high arched palate with a normal dentition. [jpma.org.pk]

• Frontal Bossing

  Patients have characteristic coarse facial features including a broad nasal base/nasal bridge as well as frontal bossing, deep set eyes, and prominent chin. Thickening of the skin can contribute to the coarse facial appearance. [immunodeficiencysearch.com]

  Percent of people who have these symptoms is not available through HPO Autosomal dominant inheritance 0000006 Chronic mucocutaneous candidiasis 0002728 Coarse facial features Coarse facial appearance 0000280 Eczematoid dermatitis 0000976 Erythema 0010783 Frontal [rarediseases.info.nih.gov]

• Coarse Face

  Hyperextensible joints/recurrent bone fractures, and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance) in early childhood. [wikidoc.org]

  In 1972, Buckley and colleagues reported infectious complications in two children who presented with severe chronic dermatitis, coarse faces, and an increased concentration of serum immunoglobulin E; hence these manifestations were termed "Buckley's Syndrome [ojrd.biomedcentral.com]

The diagnosis of Job syndrome rests on the ability of the physician to recognize the signs and symptoms followed by identification of key laboratory criteria. A detailed patient history should be obtained first, during which patients (or parents of affected children) should be inquired about the appearance of recurrent infections and skin lesions. Furthermore, the autosomal dominant pattern of inheritance suggests that the disease must be present in one of the parents, thus a positive family history might be a crucial piece of information. After a thorough physical examination, laboratory studies are the next step in the workup. A complete blood count (CBC) revealing an elevated eosinophil count and abnormally high serum immunoglobulin E (IgE) levels (exceeding > 2,000 IU/mL) are the two cardinal laboratory criteria for the diagnosis of Job syndrome [1] [2] [5]. IgE levels are elevated from birth, but may gradually reduce by adulthood, and isolated studies report that up to 20% of patients had normal IgE levels despite confirmed mutations [1] [2]. For this reason, a scoring system was designed in order to aid physicians in determining the probability of Job syndrome as the underlying cause, including all of the mentioned findings [4]. A definite diagnosis can be achieved by performing genetic testing that will confirm STAT3 mutations in the case of autosomal dominant Job syndrome, but mutations responsible for autosomal recessive forms are yet to be elucidated.

• Anergy

  There is cutaneous anergy to skin prick tests and a reduced or absent in vitro lymphocyte response to mitogens. [medcraveonline.com]

• Candida

  We observed that ex vivo T cells from subjects with HIES failed to produce IL-17, but not IL-2, tumour-necrosis factor or interferon-gamma, on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or [ncbi.nlm.nih.gov]

  Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). [hal.inria.fr]

  In most cases an excessive polyclonal IgE increase (values up to 40,000 IU/ml) is detectable in serum, with Staphylococcus and Candida specific IgE in high titers. [altmeyers.org]

  This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. [mdpi.com]

  Symptoms of Job's syndrome include eczema, recurrent abscesses, pneumonia and recurrent candida infections. Eczema usually occurs in the creases behind the ears, the back, buttocks and scalp. [pediatriconcall.com]

Thus, most AD-HIES STAT3 mutations are destabilizing; agents that modulate chaperone protein function improve STAT3 stability and activity in T cells and may provide a specific treatment. [ncbi.nlm.nih.gov]

Patient PHAa PWMa IL-2b 1 Pre-treatment 42453±2363 28112±1983 49008±3097 Post-treatment 63017±2311 50307±4763 60946±1781 2 Pre-treatment 54583±1932 43895±1108 54034±3781 Post-treatment 64961±1851 46388±3192 59689±1673 3 Pre-treatment 55257±2117 47348± [heraldopenaccess.us]

Currently, there is only one published case of Hyper IgE syndrome with DOCK8 mutation, from India, where the patient could not survive even after receiving the treatment. [americanoncology.com]

Ongoing controversies regarding etiology, diagnosis, treatment [cancertherapyadvisor.com]

Analysis of the genes associated with HIES helps with prognosis and treatment development. [fulgentgenetics.com]

Diagnosis STAT3 genetic testing to confirm diagnosis Treatment First-line antibiotics indication treat infections as they arise skin care for eczematoid dermatitis modalities bleach baths topical steroids and tacrolimus Complications ↑ Risk of lymphoma Prognosis [step2.medbullets.com]

Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented. https://www.hal.inserm.fr/inserm-00717018 Contributeur : Hervé de Villemeur <> Soumis le : mercredi [hal.inria.fr]

Prognosis Infectious pulmonary complications are the leading cause of death in patients with HIES, followed by lymphoma: Prognosis depends on the complications arising from the disease. [wikidoc.org]

Hochreutener H et al (1991) Variant of Hyper-Ig-E syndrome: The differentiation from atopic dermatitis is important because of treatment and prognosis. [altmeyers.org]

Ongoing controversies regarding etiology, diagnosis, treatment [cancertherapyadvisor.com]

Genetic testing can help establish a HIES diagnosis and determine the specific etiology. Analysis of the genes associated with HIES helps with prognosis and treatment development. [fulgentgenetics.com]

Introduction Clinical definition hyper IgE syndrome, also known as Job syndrome, is a primary immunodeficiency characterized by defective neutrophil chemotaxis ETIOLOGY Pathogenesis defect in the JAK-STAT pathway causes impaired recruitment of neutrophils [step2.medbullets.com]

There are at least two types of hyper IgE syndrome 2: autosomal dominant (STAT3 deficiency) more common caused by a mutation in STAT3 gene autosomal recessive etiology unknown maybe be associated with DOCK8 deficiency and phosphoglucomutase 3 (PGM3) deficiency [radiopaedia.org]

Abstract : ABSTRACT: Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. [hal.inria.fr]

You might also be interested in Dermatology Occurrence/Epidemiology This section has been translated automatically. Rare; about 300 cases have been described in the literature to date. Etiopathogenesis This section has been translated automatically. [altmeyers.org]

Epidemiology Frequency Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare disease. The exact incidence is unknown. It has no known associations with race, ethnicity, or gender. [emedicine.medscape.com]

Association Between Psoriasis and Sexual and Erectile Dysfunction in Epidemiologic Stud... Preview https://www.ncbi.nlm.nih.gov/pubmed/30304327 JAMA Dermatology; Molina-Leyva A, Salvador-Rodriguez L et. al. [allmedx.com]

Proteinuria ↓ ↓ ↓ ↓ - - Comined Immunodeficiency ↓ ↓ ↓ ↓ + + X linked agammaglobulinemia ↓ ↓ ↓ ↓ + - Hyperimmunoglobulin M syndrome ↑ ↓ ↓ ↓ + - Common variable immunodeficiency ↓ ↓ ↓ ↓ + - Wiskott-Aldrich syndrome ↓ ↓ ↑ ↑ - + Hyper IgE syndrome - - - ↑ - + Epidemiology [wikidoc.org]

The pathophysiologic mechanism of hyperimmunoglobulin E syndrome immunodeficiency has recently been linked to a disorder in the T helper 17 pathway and disruption of the interleukin -23/interleukin-17 axis. [pediatrics.aappublications.org]

These approaches allow for a better understanding of complex phenotypes associated with somatic mosaicisms, and present the possibility to analyze the role of B lymphocytes in the pathophysiology of this disease. [ncbi.nlm.nih.gov]

Pathophysiology The pathophysiology of Job syndrome (HIE syndrome, or hyper-IgE syndrome) is not completely understood. [8] Patients consistently have a poor, delayed hypersensitivity response to antigens. [emedicine.medscape.com]

Such a comprehensive evaluation of the coronary artery tree may contribute to the understanding of the pathophysiology and potential detection of new aspects of these diseases. [ajronline.org]

[citation needed] Pathophysiology[edit] Abnormal neutrophil chemotaxis due to decreased production of interferon gamma by T lymphocytes is thought to cause the disease.[5] Both autosomal dominant and recessive inheritance have been described:[6][7] Autosomal [en.wikipedia.org]

Primary Prevention There are no established measures for the primary prevention of hyper IgE syndrome. [wikidoc.org]

Antibiotics Antibiotics, usually trimethoprim/sulfamethoxazole, are given continuously to prevent staphylococcal infections. The rash is treated with moisturizing creams, antihistamines, and, if infection is likely, antibiotics. [merckmanuals.com]

Treatment is centred on preventing and treating infections using antibiotic, antifungal and antiviral medicines. Good skin care and hygiene to prevent infection is essential. [immunodeficiencyuk.org]

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2. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections-an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:692–702.
3. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the Hyper-IgE syndrome. N Engl J Med. 2007;18:1608–1619.
4. Grimbacher B, Schaffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. 1999;65:735–744.
5. Szczawinska-Poplonyk A, Kycler Z, Pietrucha B, Heropolitanska-Pliszka E, Breborowicz A, Gerreth K. The hyperimmunoglobulin E syndrome - clinical manifestation diversity in primary immune deficiency. Orphanet J Rare Dis. 2011;6:76.
6. 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. 2000;89:177–185.