Hyper-IgE Syndrome (HIES)

What hyper-IgE syndrome is

IgE is the antibody involved in allergies. In HIES the blood level is extremely high, often 10 to 100 times normal, but the high IgE is a marker of the immune problem rather than the cause of the symptoms.

In the classic autosomal dominant (AD) form, a change in the STAT3 gene disrupts a signaling pathway needed to make Th17 cells. These immune cells call in neutrophils (white blood cells that fight bacteria and fungi) to the skin and lungs. Without them, Staphylococcus aureus and Candida cause repeated infections at these sites. STAT3 also helps maintain bones, teeth, connective tissue and blood vessels, which explains the non-immune features.

The name "Job syndrome" comes from the biblical figure afflicted with boils.

Types of hyper-IgE syndrome

Other rare genetic causes include changes in PGM3, ZNF341, IL6ST and CARD11 genes.

Symptoms

Skin

• A pimple-like or eczema-like rash in the first weeks of life, often on the face and scalp
• Itchy, chronic eczema resembling atopic dermatitis
• Recurrent boils and abscesses, often "cold": swollen and full of pus but with little redness, warmth or pain
• Chronic candida infections of the mouth, nails and skin folds

Lungs and sinuses

• Repeated pneumonia, often caused by staph, which may produce few symptoms or little fever
• Lung cysts (pneumatoceles) and widened airways (bronchiectasis) after infections
• Fungal infection of the cysts, especially with Aspergillus (aspergillosis)
• Ear and sinus infections

Bones, teeth and face (AD-HIES)

• Baby teeth that do not fall out, so two rows of teeth may be seen
• Broken bones after minor injury
• Scoliosis (curved spine), usually in adolescence
• Hypermobile joints
• Characteristic facial features developing in childhood and adolescence: a broad nose, deep-set eyes, prominent forehead and coarse facial skin

Blood vessels

Aneurysms and twisting of medium-sized arteries, including in the heart and brain, can occur in adults with STAT3 deficiency.

How hyper-IgE syndrome is diagnosed

• Blood IgE level: usually above 2,000 IU/mL, often much higher. High IgE alone is common in severe eczema and is not enough for the diagnosis.
• Eosinophil count: often raised.
• NIH clinical scoring system: points for infections, rash, lung cysts, teeth, fractures, facial features and other findings.
• Th17 cell count: low in STAT3 deficiency.
• Genetic testing: confirms the diagnosis and the type, and allows family testing.
• Chest CT: to look for lung cysts and bronchiectasis.
• Cultures: from abscesses and sputum to guide antibiotics.

Doctors also consider other conditions that combine eczema and infections, such as severe atopic dermatitis and Wiskott-Aldrich syndrome.

Treatment

There is no medicine that corrects the STAT3 defect. Treatment focuses on preventing and controlling infections.

• Preventive antibiotics: a daily antibiotic active against staph, most commonly trimethoprim-sulfamethoxazole, taken long term.
• Preventive antifungals: for people with lung cysts or recurrent candida.
• Skin care: daily moisturizers, dilute bleach baths or antiseptic washes to reduce staph on the skin, and treatment of eczema flares.
• Early, longer treatment of infections: with a low threshold for chest imaging, because infections can be silent.
• Abscess drainage: by a surgeon when needed.
• Immunoglobulin replacement: for some people with frequent infections.
• Lung surgery: sometimes to remove infected cysts, done in specialist centers because healing is poor.
• Dental care: removal of retained baby teeth to let adult teeth come through.
• Bone health: vitamin D, calcium and monitoring for scoliosis.
• Hematopoietic stem cell transplant: standard for DOCK8 deficiency, where it cures the immune defect, and considered for selected people with severe STAT3 deficiency.

Care is best led by a primary immunodeficiency specialist center.

Outlook

With preventive antibiotics and specialist care, most people with AD-HIES live into adulthood, and many work and have families. Lung damage from past infections is the main long-term problem. DOCK8 deficiency is more severe without a transplant, with high risks from viral infections and cancer, but transplant results are good.

Frequently asked questions

Why is it called Job syndrome?

It is named after Job in the Bible, who was struck with boils from head to toe. The first patients described had repeated skin abscesses. "Job syndrome" usually refers to the autosomal dominant STAT3 form of hyper-IgE syndrome.

Is hyper-IgE syndrome inherited?

Yes. The STAT3 form is autosomal dominant, so a person with it has a 50% chance of passing it to each child, though many cases are new mutations. DOCK8 deficiency is autosomal recessive, so both parents must carry a gene change. Genetic counseling is recommended.

Does high IgE mean someone has hyper-IgE syndrome?

No. A high IgE level is much more often caused by allergies, severe eczema, asthma or parasite infections. Hyper-IgE syndrome is rare and is diagnosed only when very high IgE comes with the typical pattern of infections and other features, confirmed by genetic testing.

What is the life expectancy with hyper-IgE syndrome?

Many people with the STAT3 form now live into their 40s, 50s and beyond, especially with preventive antibiotics and early treatment of lung infections. Outlook depends mostly on the extent of lung damage. DOCK8 deficiency has a better long-term outlook after a successful stem cell transplant.