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]

  PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. [ncbi.nlm.nih.gov]

  recurrent infection syndrome is caused by mutation in the STAT3 gene (MIM.102582) (Job-Beckley syndrome). [humpath.com]

• Recurrent Upper Respiratory Infection

  In this system, patients are evaluated for the existence and severity of the following clinical and laboratory features: newborn rash, eczema, skin abscesses, recurrent upper respiratory infections, pneumonia, lung changes (cavities), candidiasis, other [primaryimmune.org]

• Rigor

  The role of prophylactic antibiotics has not been rigorously investigated, but there is general consensus in favor of use of antibiotics against Staphylococcus aureus in both HIES groups. [primaryimmune.org]

• Failure to Thrive

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

  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]

  Frequently an enteropathy is present with failure to thrive. Omenn syndrome also presents in the newborn period with rash and typically elevated serum IgE. [ncbi.nlm.nih.gov]

  […] to thrive were higher in AR-HIES patients compared to AD-HIES ones, the difference was not statistically significant, which is compatible with previous findings. [elsevier.es]

• Eczema

  Skin Affected by Hyper IgE Syndrome A newborn rash or eczema is frequently the first manifestation of AD-HIES. Pustular and eczema-like rashes usually begin within the first month of life, first affecting the face and scalp. [primaryimmune.org]

  The constellation of elevated IgE and low IgM with severe allergies or eczema should raise the possibility of DOCK8 deficiency. [oncologynurseadvisor.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]

  PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. [ncbi.nlm.nih.gov]

• Furunculosis

  ExonArray CGH Ordering Preferred Specimen: 2-5 mL Blood - Lavender Top Tube Alternative Specimen: Oral Rinse (30-40 mL) Buccal Swabs Billing CPT Codes: 81405x1, 81479x1 ICD Codes: 513 Abscess of lung and mediastinum 680 Carbuncle and furuncle Includes: boil furunculosis [genedx.com]

  The skin and soft tissue infections present as cellulitis, furunculosis, paronychia, suppurative adenitis and deep soft tissue 'cold' abscesses. Severe pulmonary infections caused by either S. aureus or H. influenzae are common. [edoj.org.eg]

  The skin and soft tissue infections may present in the form of cellulitis, furunculosis, paronychia, suppurative adenitis and \\\'cold\\\' abscesses. 1 IgE level in HIES is usually higher than 2000 IU/ml however, it does not correlate with disease severity [jpma.org.pk]

  The other types of bacterial skin infections observed included impetigo, pustulosis, and pyodermatitis in 45% of patients (n 27), folliculitis and/or furunculosis in 35% (n 21), paronychia in 23% (n 14), lymph node abscesses in 20% (n 12), and cellulitis [journals.lww.com]

  Skin infections also occur frequently - furunculosis and cellulitis may be observed early on in infancy. [ojrd.biomedcentral.com]

• Dry Skin

  Symptoms include fatigue, constipation, weight gain, depression, dry skin, and sensitivity to cold. Taking a daily oral synthetic thyroid hormone pill restores normal body functions. Myasthenia gravis. [webmd.com]

  Physical examination at admission revealed a polymorphic erythematous rash of the face and eyelids, dry skin with hyperpigmentation on the limbs, onychomycosis of the nails (Figure 1(a)), a dolichocephalic configuration of the head, dysmorphic face (Figure [hindawi.com]

  skin and itchy/irritated skin. [allmedx.com]

• 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]

  Skeletal manifestations include scoliosis, minimal trauma fractures due to osteoporosis, and hyperextensibility of the joints. Failure of exfoliation of primary teeth. [radiopaedia.org]

  Scoliosis (side-to-side curvature of the spine), joint hyperextensibility (certain joints have increased flexibility), osteoporosis (porous bony structures due to protein loss). The resultant of this cause frequent fracture after a minor trauma. [syndromespedia.com]

• 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]

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

  Hyperextensible joints, including fingers, wrists, shoulders, hips, and knees, were found in 68 percent of the patients, and three patients (Patients 7, 11, and 29) had genu valgum. [nejm.org]

• Responsiveness Decreasing

  In AD-HIES, an imbalance between Th1 and Th2 responses, decreased production/expression of IFN-γ and relatively increased level/expression of IL-4, defects in IFN-γ and IL-12 signaling pathways, insufficient expression of some chemokines and adhesion [hindawi.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]

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]

Treatment includes reducing immune system activity, usually with prednisone or another corticosteroid. [webmd.com]

Treatment There is no known cure for this condition. The goal of treatment is to prevent and treat infections with long-term use of antibiotics and antifungal medication. Sometimes, surgery is needed to drain abscesses, especially in the lungs. [cpi.org.au]

What is the treatment of Hyper IgE syndrome? Depending on the underlying condition causing the HIES, the treatment could differ. For some of these patients, skin care and prompt treatment of infections are essential. [pediatriconcall.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]

What should you tell the patient and the family about prognosis? STAT3 mutations occur spontaneously at certain spots in the gene. However, once they have occurred, they are transmitted in an autosomal dominant fashion. [oncologynurseadvisor.com]

Prognosis Few data are available on the prognosis of patients with Job syndrome (HIE syndrome, or hyper-IgE syndrome). [emedicine.medscape.com]

Variant of hyper-IgE syndrome: the differentiation from atopic dermatitis is important because of treatment and prognosis. Dermatologica 1991 ;182: 7 - 11 Citing Articles (385) Letters Article Figures/Media [nejm.org]

According to different prognosis and treatment in AR-HIES and AD-HIES, that bone marrow transplant is possible in AR-HIES, the differentiation of these two genetic types is important.6 Symptoms of the patients might vary over time, so differentiation [elsevier.es]

There are two types of HIES 2 : autosomal dominant ( STAT3 deficiency ) more common caused by a mutation in STAT3 gene autosomal recessive etiology unknown This article is concerned with the more common autosomal dominant HIES. [radiopaedia.org]

Ongoing controversies regarding etiology, diagnosis, treatment Much still needs to be learned about the etiology of this disease and the reason for the appearance of its different clinical features. [clinicaladvisor.com]

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]

The etiology & pathophysiology of Job syndrome are not completely understood. The mechanisms responsible for increased IgE production are unknown. [edoj.org.eg]

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]

Association Between Psoriasis and Sexual and Erectile Dysfunction in Epidemiologic Stud... Preview JAMA Dermatology; Molina-Leyva A, Salvador-Rodriguez L et. al. Oct 12th, 2018 - Sexual health is a major aspect of life. [allmedx.com]

STAT3 mosaicism may produce a milder phenotype. [27] Epidemiology Frequency Job syndrome (HIE syndrome, or hyper-IgE syndrome) is a rare disorder; about 250 cases have been published. [emedicine.medscape.com]

School-screening for scoliosis: a prospective epidemiological study in northwestern and central Greece. J Bone Joint Surg Am 1997 ;79: 1498 - 1503 57. Dreskin SC, Kaliner MA, Gallin JI. [nejm.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]

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]

The etiology & pathophysiology of Job syndrome are not completely understood. The mechanisms responsible for increased IgE production are unknown. [edoj.org.eg]

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]

Pathophysiology STAT3 is a major signal transduction molecule that mediates signals from a variety of immune and somatic pathways, including IL-6, IL-10, IL-11, IL-23, leukemia inhibitory factor and oncostatin M. [oncologynurseadvisor.com]

Treatment with bisphosphonates increased BMD but its role in fracture prevention remains undefined. [ncbi.nlm.nih.gov]

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

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 may include prophylactic antibiotics to prevent respiratory and skin infections, extraction of the primary teeth for healthy dentition, prompt and aggressive treatment of infections, and appropriate skin care. [columbiadoctors.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.