Job’s disease

Job’s disease (autosomal dominant hyper-IgE syndrome, Buckley syndrome) is an immunodeficiency disorder with a high level of IgE in the serum associated with recurrent skin and pulmonary infections, eczema, and eosinophilia.

Letters Ig EOverview

Job’s disease is a rare disorder inherited as an autosomal dominant pattern and caused by the mutations in the STAT3 gene. The disorder was first described back in 1966 and is characterized by a classic triad of symptoms which include high eosinophil blood count, eczema and frequent skin and respiratory infections. Furthermore, the connective tissues, teeth, and the skeleton are usually also involved. A disorder incidence is about 1/500,000 with males and females equally affected.

Causes

The disease is caused by the mutations in the STAT3 gene located on chromosome 17, namely the Src homology 2 (SH2) and DNA-binding domain (DBD) regions of this gene. This gene encodes the production one of the STAT proteins which are an essential part of the immune system, particularly the JAK-STAT signaling pathway which is necessary for normal functioning of the T helper cell type 17 (Th17). Impaired Th17 function leads to significant susceptibility of the affected person to bacterial and fungal infections.

Symptoms

The most obvious symptoms of the hyperimmunoglobulin E syndrome include frequent skin and sinopulmonary infections along with dermatitis. The rash appears early in the newborn babies, usually associated with itching and resembles atopic dermatitis. Later on, skin infections tend to worsen with the formation of the abscesses (sometimes so-called cold abscesses – these lesions are cold and nonpainful), furuncles and lymphadenitis (inflammation of the lymphatic vessels).

Individuals with Job’s syndrome are prone to pulmonary infections which, however, are rarely associated with fever and general malaise due to dysfunction of the immune system.

Fungal infections are also very common. Candida may affect the oral and vaginal mucous membranes causing candidiasis. Moreover, other fungal infections such as Cryptococcus, Histoplasmosis and Coccidioides infections may develop.

Job’s syndrome is characterized by distinctive facial features such as broad nasal base and broad nasal bridge with the frontal bossing and deep-set eyes. Additionally, skeletal and teeth abnormalities are common for this disorder.

  • Skeletal abnormalities
    1. Scoliosis (pathologic curvature of the spine);
    2. Pathologic (nontraumatic) fractures usually affecting the long bones and ribs;
    3. Hyperextensibility (increased joint mobility and movement ability) of at least one joint;
    4. Craniosynostosis (abnormal skull growth with early closing of the sutures between the bones of the skull);
    5. Retention of primary teeth, leading to double-rowed teeth;
    6. High arched palate;
  • Vascular abnormalities
    1. Aneurysms of the middle-sized arteries, for example, coronary arteries, sometimes – aortic aneurysm;
    2. Tortuosity of the arteries;
  • Brain abnormalities
    1. Chiari I malformation (an inborn disorder characterized by the herniation of the cerebellum out of the cranium through the foramen magnum);
  • Recurrent skin infections
    1. Eczema;
    2. Skin abscesses;
    3. Candidiasis;
  • Frequent pulmonary infections, infections of the upper respiratory tract and sinuses
    1. Pneumonia with the formation of pneumatocele (a cavity in the lung filled with air);
    2. Sinusitis;
    3. Otitis media;
    4. Mastoiditis;
  • Eye disorders
    1. Strabismus (cross-eye);
    2. Retinal involvement;
    3. Xanthelasmas (lipid deposits underneath the skin, may appear on the eyelids);

Diagnosis

  • Blood eosinophilia – a characteristic feature of the Job’s disease;
  • High IgE levels in the serum of above 2000 IU/mL, sometimes even higher than 5000 IU/mL. In adulthood IgE levels tend to normalize;
  • Increased erythrocyte sedimentation rate (ESR) and C-reactive protein levels are suggestive of active infection, although normal levels do not rule out infection;
  • Sputum may be collected to reveal the causative bacteria and obtain an antibiotic sensitivity test in order to choose the appropriate treatment;
  • Genetic testing is performed to confirm the presence of STAT3 mutation;
  • Chest X-ray and/or chest CT are performed to evaluate lung involvement;
  • Brain MRI may reveal the aneurysms of the brain vessels, Chiari malformation, lacunar infarcts, etc.;

Treatment

Job’s disease treatment includes administration of the antibiotics and antifungal preparations for a long term in order to prevent bacterial and fungal infection. There were also reported cases of successful administration of intravenous immunoglobulin.

When the abscesses or any other infection sites are formed surgical intervention may be necessary.

Applicable medicines

  • Trimethoprim/sulfamethoxazole is administered to prevent the development of skin and pulmonary infections.

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