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]

  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]

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

  Affected infants may also have a persistent cough, infection of the sinuses (sinusitis), and recurrent middle ear infections (otitis media). [rarediseases.org]

  Non-specific agents like levamisole and ascorbic acid may reduce recurrent infections. [ijdvl.com]

• Localized Pain

  Mild local pain should be considered a sign of possible infection, and Job syndrome patients should be taught that the typical inflammatory response does not necessarily occur. Milner JD. [emedicine.medscape.com]

• 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]

  […] 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]

  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]

• 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]

  In this condition, high serum IgE level causes multiple recurrent conditions, including, skin eruption, eczema, infections in lungs, eosinophilia 1,2. [syndromespedia.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]

  Food allergy, eczema, viral and skin infections were the major complications of AR-HIES patients. The major clinical complications of AD-HIES patients were pneumonia, skin infections and eczema. [elsevier.es]

• Furunculosis

  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]

  […] of HIES and usually begins at 2 months to 2 years of age. [1] It resembles atopic dermatitis, but is accentuated in retroauricular and hairline areas in addition to flexural involvement. [1] The skin and soft tissue infections present as cellulitis, furunculosis [ijdvl.com]

  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 [journals.lww.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]

  […] conditions including eczema, acne, dandruff, psoriasis, dry 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. [link.springer.com]

  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]

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

  Moreover, fracture sites commonly associated with osteoporosis are the vertebral bodies and femoral neck, but our patients' fractures were in the long bones, pelvis, and ribs. [nejm.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 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]

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.

• Cavitary Lesion

  It commonly presents with respiratory infections and skin findings including newborn rash, eczema, recurrent skin abscesses and ear, sinus and lung infections resulting in formation of cavitary lesions in the lungs (pneumatoceles). [primaryimmune.org]

• Anergy

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

Standard Therapies Treatment The treatment of AD-HIES is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. [rarediseases.org]

Treatment for these infections, when they occur, should be started promptly. [primaryimmune.org]

We briefly review the clinical presentation, pathogenesis, diagnosis, and treatment of HIES with special emphasis on atypical presentations leading to delayed diagnosis. This content is also available in: Español Português [lasid.org]

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]

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

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]

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]

Variant of hyper-IgE syndrome: the differentiation from atopic dermatitis is important because of treatment and prognosis. [nejm.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]

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]

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]

Although these associations were of unclear etiology, mostly related to infections and vessel diseases, it is important to consider these in HIES patients. [idoj.in]

This results in decreased chemotaxis and acute phase response that is responsible for recurrent infections. 3 The etiology of AR-HIES is under debate. [jpma.org.pk]

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]

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]

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]

Epidemiology and consequences of osteoporotic fractures. Aging Skelet. 1999;359:339–47. Article Google Scholar Sowerwine KJ, Shaw PA, Gu W, Ling JC, Collins MT, Darnell DN, et al. Bone density and fractures in autosomal dominant hyper IgE syndrome. [link.springer.com]

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]

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]

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

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]

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]

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]

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]

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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.