Job syndrome

Job syndrome is a condition that affects several body systems, particularly the immune system. Recurrent infections are common in people with this condition. Affected individuals tend to have frequent bouts of pneumonia, which are caused by certain kinds of bacteria that infect the lungs and cause inflammation. Recurrent skin infections and an inflammatory skin disorder called eczema are also very common in Job syndrome. These skin problems cause rashes, blisters, collections of pus (abscesses), open sores, and scaling.

Job syndrome is characterized by abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood, which is why this condition is also known as hyper-IgE syndrome. IgE triggers an immune response against foreign invaders in the body, particularly parasitic worms, and plays a role in allergies. It is unclear why people with Job syndrome have such high levels of IgE.

This condition also affects other parts of the body, including the bones and teeth. Many people with Job syndrome have skeletal abnormalities such as an unusually large range of joint movement (hyperextensibility), an abnormal curvature of the spine (scoliosis), reduced bone density (osteopenia), and a tendency for bones to fracture easily. Dental abnormalities are also characteristic of this condition. The primary (baby) teeth do not fall out at the usual time during childhood, but are retained as the adult teeth grow in. Other signs and symptoms of Job syndrome can include distinctive facial features and structural abnormalities of the brain, which typically do not affect a person's intelligence.

This condition is rare, affecting fewer than 1 per million people. About 250 people with Job syndrome have been reported in the medical literature.

Mutations in the STAT3 gene cause Job syndrome. This gene provides instructions for making a protein that plays an important role in several body systems. The STAT3 protein is involved in many cellular functions, including cell growth and division, cell movement, and the self-destruction of cells (apoptosis). To carry out these roles, the STAT3 protein attaches to DNA and helps control the activity of particular genes.

Little is known about the effects of STAT3 mutations on the body's cells and tissues. Changes in this gene alter the structure and function of the STAT3 protein, impairing its ability to control the activity of other genes. The defective protein disrupts cellular functions such as immune system regulation. The resulting immune system abnormalities make people with Job syndrome highly susceptible to infections. The STAT3 protein is also involved in the formation of cells that build and break down bone tissue, which could help explain why STAT3 mutations lead to the skeletal and dental abnormalities characteristic of this condition.

When Job syndrome is not caused by STAT3 mutations, the genetic cause of the condition is unknown.

Job syndrome often has an autosomal dominant pattern of inheritance, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In about half of all cases, an affected person inherits a STAT3 mutation from an affected parent. Other cases result from new mutations in this gene. These cases occur in people with no history of the disorder in their family.

Researchers have also described an autosomal recessive form of Job syndrome. Autosomal recessive inheritance means both copies of a gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. The autosomal recessive form of Job syndrome is less common than the autosomal dominant form and has a different pattern of signs and symptoms. It is associated with fewer bacterial lung infections, more severe viral infections, serious complications involving the nervous system, and no skeletal or dental abnormalities. No STAT3 mutations have been found in people with the autosomal recessive form of this condition.