Autosomal dominant hyper IgE syndrome

Other Names: AD-HIES; Hyper Ig E syndrome, autosomal dominant; HIES autosomal dominant; Hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant; AD hyperimmunoglobulin E syndrome; Job syndrome autosomal dominant

Autosomal dominant hyper IgE syndrome (AD-HIES), formerly known as Job syndrome, affects several body systems including the immune system. AD-HIES is characterized by abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood.

IgE normally triggers an immune response against foreign invaders in the body, particularly parasitic worms, and is involved in allergies. However, IgE is not needed for these roles in people with AD-HIES, and it is unclear why affected individuals have such high levels of the protein without having allergies.

Epidemiology

AD-HIES is rare, affecting fewer than 1 per million people worldwide.

Cause

Mutations in the STAT3 gene cause most cases of AD-HIES. This gene provides instructions for making a protein that plays important roles in several body systems. To carry out its roles, the STAT3 protein attaches to DNA and helps control the activity of particular genes. In the immune system, the STAT3 protein regulates genes that are involved in the maturation of immune system cells, especially certain types of T cells. T cells and other immune system cells help control the body's response to foreign invaders such as bacteria and fungi.

Changes in the STAT3 gene alter the structure and function of the STAT3 protein, impairing its ability to control the activity of other genes. A shortage of functional STAT3 blocks the maturation of T cells (specifically a subset known as Th17 cells) and other immune cells. The resulting immune system abnormalities make people with AD-HIES highly susceptible to infections, particularly bacterial and fungal infections of the lungs and skin. The STAT3 protein is also involved in the formation of cells that build and break down bone tissue, which could help explain why STAT3 gene mutations lead to the skeletal and dental abnormalities characteristic of this condition. It is unclear how STAT3 gene mutations lead to increased IgE levels.

Mutations in the ZNF341 gene cause a disorder similar to AD-HIES but with a different pattern of inheritance. When the STAT3 gene is involved, one altered copy of the gene is sufficient to cause the disorder (which is known as autosomal dominant inheritance). In contrast, when the ZNF341 gene is involved, both copies of the gene are altered (which is known as autosomal recessive inheritance).

The ZNF341 gene provides instructions for making a protein that appears to control the activity of the STAT3 gene. ZNF341 gene mutations, which prevent production of functional ZNF341 protein, result in a shortage of STAT3 protein, leading to immune system problems similar to those caused by STAT3 gene mutations.

AD-HIES is thought to be caused by mutations in other genes that have not been definitively linked to the condition.

Inheritance

AD-HIES has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In about half of cases caused by STAT3 gene mutations an affected person inherits the mutation from one affected parent. The other half result from new mutations in the gene and occur in people with no history of the disorder in their family.

A similar condition caused by mutations in the ZNF341 gene has an autosomal recessive pattern of inheritance, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

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. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). However, excessive inflammation can damage body tissues. Recurring pneumonia often results in the formation of air-filled cysts (pneumatoceles) in the lungs. Frequent skin infections and an inflammatory skin disorder called eczema are also very common in AD-HIES. These skin problems cause rashes, blisters, accumulations of pus (abscesses), open sores, and scaling.

AD-HIES also affects other parts of the body, including the bones and teeth. Many people with AD-HIES 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. A common dental abnormality in this condition is that 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 AD-HIES can include abnormalities of the arteries that supply blood to the heart muscle (coronary arteries), distinctive facial features, and structural abnormalities of the brain, which do not affect a person's intelligence.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Atelectasis(Partial or complete collapse of part or entire lung)
• Eczema
• Generalized abnormality of skin(Generalised abnormality of skin)
• Increased circulating IgE level
• Pruritus(Itching)
• Recurrent respiratory infections(Frequent respiratory infections)
• Skin rash
• Skin ulcer(Open skin sore)

30%-79% of people have these symptoms

• Abnormal hair morphology(Abnormality of the hair)
• Chronic otitis media(Chronic infections of the middle ear)
• Cleft palate(Cleft roof of mouth)
• Cough(Coughing)
• Deeply set eye(Deep set eye)
• Delayed eruption of teeth(Delayed eruption)
• Dystrophic fingernails(Poor fingernail formation)
• Eosinophilia(High blood eosinophil count)
• Gingivitis(Inflamed gums)
• Joint hyperflexibility(Joints move beyond expected range of motion)
• Osteopenia
• Papule
• Paronychia
• Prominent forehead(Pronounced forehead)
• Recurrent fractures(Increased fracture rate)
• Scoliosis
• Wide nasal bridge(Broad nasal bridge)

5%-29% of people have these symptoms

• Cellulitis(Bacterial infection of skin)
• Craniosynostosis
• Dilatation(Wider than typical opening or gap)
• Fever
• Lymphoma(Cancer of lymphatic system)
• Osteomyelitis(Bone infection)
• Skin vesicle

1%-4% of people have these symptoms

• Arnold-Chiari type I malformation

Diagnosis

The diagnosis of autosomal dominant hyper IgE syndrome (AD-HIES) is most often made based on a combination of clinical and laboratory findings. Diagnostic guidelines have been developed that include both immunologic /infectious manifestations and skeletal/connective tissue abnormalities. Molecular genetic testing of the STAT3 gene confirms the diagnosis.

Treatment

The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections. Use of antibiotics and antifungal agents depends on the nature of the infection and the extent of involvement. Antiseptic therapies for the skin such as dilute bleach baths and chlorhexidine are beneficial.

Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. There is no known treatment or prevention for the nonimmunologic characteristics, although optimization of calcium and vitamin D intake may be considered to improve bone health. The role of hematopoietic cell transplantation (HSCT) in STAT3-HIES is emerging; while successful transplant recipients have improved infection phenotype, the effect of HSCT on the nonimmunologic aspects of the disease remains unclear.

NIH genetic and rare disease info

• NIH info on Autosomal dominant hyper IgE syndrome

Autosomal dominant hyper IgE syndrome is a rare disease.

Autosomal dominant hyper IgE syndrome Resources
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