What are the early warning signs of a serious infection in someone with AD‑HIES, and when should I seek emergency care?

If you notice sudden high fever (above 38.5°C), rapid breathing, chest pain, or a cough that produces thick, foul‑smelling sputum, these could signal a severe lung infection or abscess. A sudden increase in pain or swelling in a joint, or a new, rapidly expanding skin abscess, also warrants immediate evaluation. Call your doctor or go to the emergency department if you experience any of these symptoms, especially if they worsen within a few hours.

Are there specific vaccinations or infection prevention strategies recommended for AD‑HIES patients?

Because people with AD‑HIES are prone to bacterial infections, your immunization schedule should include the pneumococcal conjugate vaccine (PCV13) and the annual influenza shot. Discuss with your provider about the use of the recombinant zoster vaccine if you are over 50. Additionally, practice good hand hygiene, avoid close contact with sick individuals, and keep up-to-date on routine vaccines to reduce infection risk.

How can I manage the high IgE levels and prevent allergic reactions, even though I don’t have typical allergies?

High IgE in AD‑HIES does not usually cause classic allergic symptoms, but it can increase sensitivity to certain medications or environmental triggers. Work with an allergist to identify any specific triggers, keep a symptom diary, and use antihistamines only when prescribed. Avoid known irritants such as strong perfumes, dust, and certain foods if they seem to worsen skin or respiratory symptoms.

What dental or skeletal issues should I monitor, and what specialists should I see regularly?

D‑HIES can cause early tooth loss, enamel hypoplasia, and joint hypermobility. Schedule annual dental check‑ups that include X‑rays to monitor tooth development and root integrity. For skeletal concerns, see an orthopedic specialist every 1–2 years for joint assessment and bone density testing, especially if you have a history of fractures or significant joint pain.

Autosomal Dominant Hyper-IgE Syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES), also known as Job syndrome, is a rare multi-system condition primarily affecting the immune system, characterized by recurrent infections, abnormally high levels of immunoglobulin E (IgE), and skeletal and dental abnormalities.

Overview

Autosomal dominant hyper-IgE syndrome (AD-HIES), formerly known as Job syndrome, is a condition that affects several body systems, particularly the immune system. AD-HIES is rare, affecting fewer than 1 per million people worldwide.

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 sinus 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.

For unknown reasons, people with AD-HIES have 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.

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 (hypermobility), 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 artery abnormalities), distinctive facial features, and structural abnormalities of the brain, which do not affect a person's intelligence.

Causes & Risk Factors

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.

Learn more about the genes associated with Autosomal dominant hyper-IgE syndrome

STAT3
ZNF341

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 de novo mutations 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.

Other Names for This Condition

AD-HIES
Autosomal dominant HIES
Autosomal dominant hyper-IgE recurrent infection syndrome
Autosomal dominant hyperimmunoglobulin E recurrent infection syndrome
Autosomal dominant Job syndrome
Buckley syndrome
Job syndrome
Job's syndrome
Job-Buckley syndrome
STAT3 deficiency
STAT3-deficient hyper IgE syndrome