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].

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.

Treatment for Hyper-IgE Syndrome is primarily supportive and focuses on managing infections and other symptoms. Antibiotics are used to treat and prevent bacterial infections. Antifungal medications may be prescribed for fungal infections. Good skin care and topical treatments can help manage eczema. In some cases, immunomodulatory therapies, such as interferon-gamma, may be considered. Regular follow-up with a multidisciplinary team is essential to address the various aspects of the disease.

The prognosis for individuals with Hyper-IgE Syndrome varies depending on the severity of the condition and the effectiveness of treatment. With appropriate management, many patients can lead relatively normal lives. However, recurrent infections and complications can impact quality of life and may lead to chronic lung disease or other long-term health issues. Early diagnosis and comprehensive care are key to improving outcomes.

Hyper-IgE Syndrome is primarily caused by genetic mutations. The most common form, autosomal dominant HIES, is associated with mutations in the STAT3 gene, which plays a critical role in immune system regulation. There is also an autosomal recessive form of the syndrome, which is less common and involves different genetic mutations. These genetic changes disrupt normal immune function, leading to the characteristic symptoms of the disease.

Hyper-IgE Syndrome is a rare condition, with an estimated prevalence of less than 1 in 1,000,000 individuals. It affects both males and females and can occur in various ethnic groups. Due to its rarity, the syndrome is often underdiagnosed or misdiagnosed, highlighting the importance of awareness among healthcare professionals.

The pathophysiology of Hyper-IgE Syndrome involves a complex interplay of immune system dysfunctions. The elevated IgE levels are a hallmark of the disease, but the exact mechanisms leading to this increase are not fully understood. Mutations in the STAT3 gene impair the development and function of certain immune cells, resulting in increased susceptibility to infections and abnormal inflammatory responses. This immune dysregulation also contributes to the connective tissue and skeletal abnormalities seen in patients.

Currently, there are no specific measures to prevent Hyper-IgE Syndrome, as it is a genetic disorder. Genetic counseling may be beneficial for families with a history of the condition to understand the risks and implications. Preventive strategies focus on reducing the risk of infections through good hygiene practices, vaccination, and prophylactic antibiotics when appropriate.

Hyper-IgE Syndrome is a rare immunodeficiency disorder characterized by high IgE levels, recurrent infections, and various physical abnormalities. Diagnosis involves clinical evaluation, laboratory tests, and genetic analysis. Treatment is supportive, focusing on infection management and symptom relief. While the condition poses significant challenges, early diagnosis and comprehensive care can improve patient outcomes. Understanding the genetic basis and immune dysfunctions in HIES is crucial for developing future therapies.

If you or a loved one has been diagnosed with Hyper-IgE Syndrome, it's important to work closely with a healthcare team to manage the condition. Regular medical check-ups, prompt treatment of infections, and adherence to prescribed therapies are essential. Educating yourself about the disease can empower you to make informed decisions about your care. Support groups and patient organizations can also provide valuable resources and connect you with others facing similar challenges.

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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.