Hyper IgE syndrome (HIES) is a rare primary immunodeficiency defined by a triad of severe eczema, recurrent skin infections caused by staph bacteria, and recurrent pneumonia. It affects roughly 1 in 100,000 to 1 in 1,000,000 people worldwide, with only about 6 to 10 new cases identified per year globally. The condition is sometimes called Job syndrome, a biblical reference to the boils that afflicted Job. Beyond the immune system problems, HIES causes a distinctive pattern of skeletal, dental, and facial abnormalities that help doctors recognize it.
What Causes Hyper IgE Syndrome
The most common form is caused by mutations in a gene called STAT3, which provides instructions for a protein involved in immune signaling. STAT3 acts as a relay inside cells: when the body detects an infection, chemical messengers (cytokines) dock onto cells and trigger STAT3 to carry the signal into the nucleus, turning on genes needed for a proper immune response. In people with HIES, mutations in STAT3 disrupt this relay. The result is a paradox: the body overproduces some inflammatory signals while failing to respond normally to others, particularly those routed through a key infection-fighting messenger called interleukin-6.
This form is inherited in an autosomal dominant pattern, meaning a single copy of the mutated gene from one parent is enough to cause the disease. Many cases are also sporadic, arising from new mutations with no family history. Researchers have identified 18 distinct STAT3 mutations in HIES patients, with five “hot spots” that account for the majority of cases. These mutations cluster in two critical parts of the STAT3 protein: the region that binds DNA and the region that allows the protein to activate.
A Second Form: DOCK8 Deficiency
A less common variant, previously called autosomal recessive hyper IgE syndrome, is caused by mutations in a different gene called DOCK8. This form requires inheriting a defective copy from both parents. DOCK8 deficiency produces some overlapping features, like very high IgE levels and eczema, but its hallmark is severe, persistent viral skin infections rather than the bacterial infections seen in STAT3 HIES. People with DOCK8 deficiency have fewer immune cells overall, and those cells struggle to move through dense tissues like the skin, causing them to fragment and die. This form also carries a higher risk of allergies, asthma, and certain cancers.
Skin and Infection Symptoms
Skin problems typically appear within the first few weeks of life, often starting as an itchy, eczema-like rash on the scalp and face. This rash quickly becomes infected with Staphylococcus aureus, producing weeping, crusty lesions. One of the most recognizable features is “cold” skin abscesses: deep pockets of infection that lack the redness, warmth, and tenderness you would normally expect. Because the immune system cannot mount a proper inflammatory response, these abscesses can grow large before anyone notices them.
Candida (yeast) infections are also common, affecting the skin, nails, and mucous membranes of the mouth and throat.
Lung Complications
Recurrent pneumonia is one of the defining features of HIES. Staphylococcus aureus is the most frequently isolated pathogen, found in about 57% of pulmonary cases, followed by Streptococcus pneumoniae and Haemophilus influenzae. Pneumonia in HIES patients often begins in early childhood and tends to be more destructive than typical pneumonia because the body’s tissue repair mechanisms are impaired.
This impaired healing leads to pneumatoceles, which are air-filled cysts that form in the lungs after infection. In a review of HIES cases, about 12% of patients developed pneumatoceles and 5% developed bronchiectasis, a condition where the airways become permanently widened and scarred. These structural changes create new problems: the damaged lung tissue becomes a breeding ground for opportunistic organisms like Aspergillus (a mold) and Pseudomonas bacteria that are difficult to treat. Tuberculosis and other mycobacterial infections have also been reported. Some patients develop serious complications including lung abscesses, empyema (pus collecting around the lungs), and pneumothorax (collapsed lung).
Skeletal, Dental, and Facial Features
HIES affects far more than the immune system. About 68% of patients have hypermobile joints, which can lead to early-onset degenerative joint disease. Roughly 60% develop scoliosis of varying severity. Bone density is reduced, and approximately 50% of patients experience fractures from minimal trauma, particularly in the long bones and ribs.
One of the most distinctive features is failure to shed baby teeth. About 72% of patients retain their primary teeth because the roots do not resorb normally, which can prevent permanent teeth from coming in on schedule. Many patients also develop a characteristic facial appearance with a broad nose, prominent forehead, and rough skin texture. A high-arched palate is another common finding.
How HIES Is Diagnosed
Diagnosis relies on a combination of lab work, clinical features, and, increasingly, genetic testing. The two most consistent lab findings are a serum IgE level above 2,000 IU/mL (normal is typically under 100) and elevated eosinophils, a type of white blood cell. Both abnormalities can be present from birth.
The National Institutes of Health developed a clinical scoring system that assigns points across more than 20 features, including the number of pneumonia episodes over a lifetime, the presence of skin abscesses, retained baby teeth, scoliosis, fractures, newborn rash, candida infections, and characteristic facial features. Higher scores increase diagnostic confidence. However, because young children may not yet have developed the full range of symptoms, the scoring system includes an age correction factor. Genetic testing for STAT3 mutations now provides definitive confirmation in most cases.
Treatment and Daily Management
There is no cure for HIES, so management focuses on preventing infections and treating complications early. The cornerstone of care is daily preventive antibiotics targeting Staphylococcus aureus, typically taken twice a day. This prophylaxis significantly reduces the frequency of skin abscesses and pneumonia episodes. For patients living in regions where a fungal infection called coccidioidomycosis (valley fever) is common, preventive antifungal medication may also be recommended.
Skin care is a daily commitment. Keeping eczema under control with moisturizers and topical treatments reduces the risk of bacterial superinfection. Prompt treatment of any new skin infection before it spreads to deeper tissues is critical. Lung health requires ongoing monitoring, typically with periodic imaging to catch pneumatoceles or bronchiectasis early. When structural lung damage does occur, long-term suppressive antibiotics or antifungals may be needed to prevent colonization by Aspergillus or Pseudomonas.
Bone health management includes monitoring bone density and addressing fracture risk. Dental care often involves extracting retained primary teeth to allow permanent teeth to erupt normally. Scoliosis may require bracing or, in severe cases, surgical correction.
Long-Term Outlook
With consistent preventive care, many people with HIES live into adulthood. The greatest threats to survival are lung complications: progressive structural damage from repeated infections, invasive fungal disease in damaged lung tissue, and, rarely, lymphoma. The shift toward early diagnosis, routine preventive antibiotics, and aggressive management of lung infections has improved outcomes considerably compared with earlier decades, when many patients died young from overwhelming pneumonia or its complications. For DOCK8 deficiency specifically, bone marrow transplant has emerged as a potentially curative option, though it carries its own significant risks.