Job syndrome is a multisystem hereditary disease based on primary immunodeficiency. Occurs due to mutations in STAT3, TYK2, DOCK8 genes. The classic triad of symptoms includes eczematous dermatitis, recurrent skin infections, and infectious lung lesions. There are also deformations of facial features, bone anomalies, violations of the formation of teeth. To diagnose the Gob syndrome, an immunological blood test and genetic testing are carried out. Patients are prescribed supportive treatment, including antibiotics, antimycotics, antiallergic agents.
ICD 10
D82.4 Hyperimmunoglobulin E syndrome
General information
Job syndrome (Job) has a second name “hyperimmunoglobulinemia E”, which reflects the main pathogenetic feature of the disease. Pathology belongs to the orphan class, in the medical literature there is information about 250 cases of the syndrome worldwide. The disease was first described by the American pediatrician Davis Starkey in 1966, when its main clinical signs were established. The connection with hyperproduction of IgE was revealed in 1972 by the doctor Rebecca Barkley. The genetic background of the disease was discovered in 2007 .
Causes
Job syndrome has two types of inheritance. In the autosomal dominant variant, the disease is caused by a mutation in the STAT3 gene. In this case, the risk of having a sick child is 50%, regardless of gender, if one of the parents is sick. The autosomal recessive variant is characterized by defects in the TYK2 or DOCK8 genes. For the development of pathology, it is required that both parents be carriers of mutant alleles, while the probability of inheritance of the syndrome exists in 25% of children.
Pathogenesis
The STAT3 gene acts as a signal inducer for several types of interleukins that are involved in the formation of an immune response. This signaling pathway controls the activity of pro-inflammatory and anti-inflammatory molecules. With a mutation of the gene, the differentiation of Th-17 T-lymphocytes is disrupted, the course of immunological reactions changes, as a result of which the immune system ineffectively fights mycoses, bacterial infections.
Frequent lesions of the skin and lungs in Job syndrome are explained by the fact that these tissues are most strongly dependent on the presence of Th-17, without which they cannot realize their local antibacterial mechanisms. As a result, the susceptibility to infections increases, their prolonged, recurrent course is observed. Non-immunological aspects of the syndrome are caused by a violation of tissue remodeling, vascular pathologies.
Symptoms
Clinical manifestations of Job syndrome occur in infancy. Immediately after birth, typical anomalies of the structure of the skull are revealed: children have rough facial features, protruding nose and chin, wide wings of the nose. As they grow older, facial asymmetry and rough skin become more noticeable. Pathologies of the musculoskeletal system are complemented by hyperextension of ligaments, osteopenia, degenerative joint lesions.
A pathognomonic sign of Job syndrome is multiple pustular or eczematous rashes that occur in the first weeks of life. At first they are localized on the skin of the face and scalp, later they spread throughout the body. Over time, the rash transforms into eczematous dermatitis associated with Staphylococcus aureus. The formation of cold abscesses is specific, in which there is no redness of the skin, the local temperature does not rise.
Hyperimmunoglobulinemia E is also manifested by recurrent infections of the paranasal sinuses, bronchi, lungs. They are caused by Staphylococcus aureus, pneumococci, hemophilic bacilli, and the greatest danger is infection with Pseudomonas aeruginosa. Pneumonia is difficult to treat with standard antibiotics, due to constant immunosuppression, it is possible to attach a fungal infection with the development of lung aspergillosis.
Complications
Job syndrome is characterized by a severe course, all body systems are involved in the pathological process. The autosomal dominant type of the disease is characterized by the destruction of teeth, violations of the timing of the change of dentition, enamel hypoplasia. Lesions of the musculoskeletal system are represented by scoliosis, increased bone fragility and the risk of fractures. Vascular anomalies — aneurysms – often occur.
The autosomal recessive type of the syndrome is complicated by allergic disorders: pollinosis, atopic dermatitis, bronchial asthma. In such cases, a typical “allergic march” is clearly traced. Occasionally there are neurological complications. This form of the disease is more dangerous because patients have a high probability of developing lymphoma, skin cancer.
The main cause of death in patients with Job syndrome remains severe bacterial lung infections, which are fraught with sepsis, septicemia, and pulmonary bleeding. Chronic pneumonia is often accompanied by the formation of pneumatocele — air cysts that disrupt the processes of gas exchange. The defeat of the bronchi ends with bronchiectatic disease with frequent exacerbations, which is also fraught with generalization of infection and death.
Diagnostics
The examination of the patient is carried out by a neonatologist or pediatrician. During external examination, numerous rashes, boils, cold abscesses attract attention. It is of great importance to clarify the family history, to determine the degree of risk of Job’s disease in a child. The following laboratory and instrumental methods are used to accurately diagnose the syndrome:
- Immunological tests. A standard blood test shows high eosinophilia, and with an in-depth study of the immune system, the level of serum IgE is increased to more than 2000 IU/ml (4800 mcg/ l). There may be deviations in the ratio of lymphocyte fractions in the immunogram. Indicators of other immunoglobulins are normal.
- Genetic diagnostics. Genome sequencing and fluorescent hybridization are performed in specialized centers to clarify the molecular mechanisms of mutation, to determine the variant of inheritance of the syndrome. In routine practice, it is possible to confirm the diagnosis without the results of genetic examination.
- Lung x-ray. The study is performed to identify signs of chronic bronchitis, bronchiectasis, pneumonia. In order to visualize the pneumatocele in more detail, foci of bronchial deformity, a CT scan of the lungs is prescribed. According to the indications, invasive techniques are used: bronchoscopy, bronchography, lung tissue biopsy.
- Skin examination. Histological analysis of biopsies reveals an eosinophilic infiltrate. To identify the causative agent of dermatological infections, microscopy of the separated pustules, sowing of biomaterial for nutrients, a test for antibiotic sensitivity is carried out.
Treatment
Conservative therapy
Preventive treatment includes long-term use of anti-staphylococcal antibiotics (dicloxacillin, trimethoprim-sulfamethoxazole) to reduce the risk of skin and respiratory infections. Antifungal drugs are indicated to prevent mycoses against the background of immunosuppression aggravated by antibiotic therapy. Taking into account the clinical symptoms are used:
- Additional antibiotics. Antibacterial agents from the group of glycopeptides are prescribed for the development of staphylococcal pneumonia. Cephalosporins are recommended for the treatment of pneumonia caused by hemophilic bacillus.
- Gamma interferon. The drug is effective in severe recurrent infections that pose a threat to life, do not respond well to standard protocols of antibiotic therapy.
- Steroids. They are used as topical preparations (ointments, creams) to combat eczema rashes, reduce skin symptoms, and relieve itching. Therapy is supplemented with calcineurin inhibitors, H1-histamine blockers.
Experimental treatment
Bone marrow transplantation is considered as a promising therapy option that reduces the intensity of clinical manifestations, increases the level of resistance of the body. There are reports in the literature about the successful use of monoclonal antibodies to neutralize the excess of immunoglobulin E in the blood serum. A number of authors speak about the effectiveness of plasmapheresis in the treatment of Job syndrome.
Prognosis and prevention
With adequate complex therapy, it is possible to extend the term and improve the quality of life of patients. However, despite the improvement of the treatment protocols of the syndrome, most patients die at the age of 20-40 years from secondary infectious complications. Primary prevention has not been developed due to the rarity of the disease. Secondary preventive measures include early diagnosis, complex therapy, and follow-up of patients with Job syndrome.