Job's syndrome, or hyper-IgE syndrome, is a rare disease of genetic origin resulting in immunodeficiency. People with Job's syndrome are characterized by a specific face appearance, excessive joint mobility, and bone fractures. What are the other symptoms of Job's disease? What is the treatment?

Job's syndrome , also known as hyper-IgE syndrome (HIES) or Job's syndrome, is a rare genetic disease that results in primary immunodeficiency .

The disease is characterized by a triad of symptoms: high levels of IgE antibodies in the blood, recurrent infections of the upper respiratory tract and skin lesions.

Job's syndrome occurs with a frequency of 1: 500,000 - 1: 1,000,000 cases. The disease is very rare and about 250 cases of the disease have been described worldwide. There was no evidence of a higher incidence of Job's syndrome in either gender or ethnic group.

Job's syndrome - causes and forms of the disease

Until 2006, Job's syndrome was the last of the primary immunodeficiencies of unknown cause. However, it is currently known that it is a genetic disease caused by mutations in selected genes related to signal transduction in the cell. The risk of developing the disease in a child of a person suffering from Job's syndrome is 50%.

Due to the way of inheritance of mutations, Job's syndrome occurs in two clinical forms:

  • autosomal dominant form (AD-HIES, autosomal dominant), which means that one copy of the mutated gene is enough to manifest the disease; this form of the disease is also the most common
  • autosomal recessive form (AR-HIES); which means that for the disease to manifest itself, it is necessary to have two copies of the mutant gene

Five different mutations in the STAT3 gene, coding for a protein of the same name, have been described in patients with AD-HIES of Job's syndrome. STAT3 is a type of signaling molecule that transmits information from receptors on the cell surface to the nucleus. The consequence of the mutation is a change in the structure of the STAT3 protein and the inability to transmit correct signals in the cell.

The STAT5 signal has a particular start in the process of differentiation of Th17 cells responsible for reactionsdefense against microbes. Therefore, people with Job's syndrome are susceptible to infections. However, it is not entirely clear how the STAT3 gene mutation increases the level of IgE antibodies in the blood.

The rarer form of Job's syndrome, AR-HIES, is usually caused by mutations in the DOCK8 gene. The DOCK8 protein is, among others, responsible for maintaining the proper structure of T lymphocytes and NK cells, which are involved in the processes of recognizing and neutralizing microorganisms, especially viruses.

Mutations result in reduced or no DOCK8 protein synthesis, resulting in cells that are abnormal in shape, preventing them from fulfilling their functions. This form of Job's syndrome is also caused by mutations in the TYK2 gene, which encodes the tyrosine kinase 2. Like STAT3, the TYK2 protein is a type of molecular transmitter in the cell.

Job's syndrome - symptoms

  • skin blemishes (95%)
  • characteristic facial features (85%); people with Job's syndrome have a prominent forehead, a wide bridge of the nose and an asymmetrical face
  • recurrent sinusitis or otitis media (80%)
  • neonatal erythema (80%)
  • skin abscesses (80%)
  • pneumonia (70%)
  • bronchiectasis (70%)
  • excessive mobility in the joints (70%)
  • persistent milk teeth (70%)
  • pathological bone fractures (65%)
  • coronary artery abnormalities (60%)
  • scoliosis (60%)
  • onychomycosis (50%)
  • mucosal dermatitis (30%)
  • lymphomas (5%)
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Job's syndrome - diagnostics

The diagnosis of Job's syndrome is based on the presence of characteristic symptoms and a very high concentration of IgE antibodies in the blood (over 1000 IU / ml). However, it does not correlate with the severity of the disease symptoms. Increased concentration of IgE antibodies should be differentiated from atopy, parasitic infections, pulmonary aspergillosis, myeloma and other genetic syndromes such as Netherton, Wiskott-Aldrich or Omenn syndromes.

The level of IgM, IgG and IgA antibodies in people with Job's syndrome may be low or normal. Eosinophilia may be present in the blood count.
In the diagnosis of the disease, the points scale according to Grimbacher is used.

A score below 15 points with high probabilityexcludes Job's syndrome, a result in the range of 16-39 points is a possible disease, a result of 40-59 points confirms the diagnosis with high probability. On the other hand, a result above 60 points is practically confirmed by Job's syndrome and is an indication for a molecular test confirming the diagnosis.

Job's syndrome - treatment

Due to the genetic basis of the disease, it is currently not possible to treat it causally. Symptomatic treatment is mainly based on aggressive antibiotic therapy for infections such as Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae.

References

  1. Grzela K. Hyper-IgE syndrome (HIES) - clinical implications. Post-Diploma Pediatrics 2012, 04.
  2. Freeman A.F. and Holland S.M. Clinical symptoms of the hyper-IgE syndrome. Post-Diploma Dermatology 2012, 3 (2), 24-33.
  3. Al-Shaikhly T. and Ochs H.D. Hyper IgE syndromes: clinical and molecular characteristics. Immunol Cell Biol. 2022, 28.
About the authorKarolina Karabin, MD, PhD, molecular biologist, laboratory diagnostician, Cambridge Diagnostics Polska A biologist by profession, specializing in microbiology, and a laboratory diagnostician with over 10 years of experience in laboratory work. A graduate of the College of Molecular Medicine and a member of the Polish Society of Human Genetics. Head of research grants at the Laboratory of Molecular Diagnostics at the Department of Hematology, Oncology and Internal Diseases of the Medical University of Warsaw. She defended the title of doctor of medical sciences in the field of medical biology at the 1st Faculty of Medicine of the Medical University of Warsaw. Author of many scientific and popular science works in the field of laboratory diagnostics, molecular biology and nutrition. On a daily basis, as a specialist in the field of laboratory diagnostics, he runs the content department at Cambridge Diagnostics Polska and cooperates with a team of nutritionists at the CD Dietary Clinic. He shares his practical knowledge on diagnostics and diet therapy of diseases with specialists at conferences, training sessions, and in magazines and websites. She is particularly interested in the influence of modern lifestyle on molecular processes in the body.

Category:

Genetic diseases