Many different syndromes are known to lead to high levels of an antibody called immunoglobulin E, or IgE. Many more such syndromes likely remain unknown. Collectively, these conditions are called hyper-IgE syndromes, or HIES. Other conditions, such as severe eczema, can lead to extremely high IgE levels that are not caused by a syndrome at all.
To determine whether a person with a high level of IgE has a known syndrome causing it, physicians assess the individual’s other symptoms and search for the causative genetic mutation. Each set of mutations causes a specific syndrome, including autosomal-dominant CARD11 deficiency, DOCK8 deficiency, IL6R deficiency, IL6ST deficiency, PGM3 deficiency, STAT3 dominant-negative disease and many others.
Autosomal-Dominant CARD11 Deficiency
In 2017, NIH researchers showed that autosomal dominant mutations in a gene called CARD11 could lead to a loss of function of the CARD11 protein, impairing it from helping activate white blood cells normally. People with autosomal-dominant CARD11 deficiency can develop severe allergic disease, including eczema and food allergies; viral and bacterial infections of the skin; respiratory tract infections; and autoimmunity.
DOCK8 deficiency is an autosomal recessive syndrome associated with high IgE and is named for the mutated gene responsible for the disease. People with this syndrome have lower-than-normal numbers of immune cells, which have a diminished capacity to move through dense tissues like the skin. These abnormalities lead to recurrent viral infections of the skin and respiratory system. People with DOCK8 deficiency also typically have severe allergies, asthma, and an elevated risk for some types of cancer. Read more about this syndrome.
IL-6 Receptor Deficiency
IL-6 receptor (IL6R) deficiency is an autosomal recessive syndrome caused by the absence of the IL-6 receptor, a critical molecule located on the surface of cells and involved in inflammatory responses. The absence of this receptor leads to severe skin infections and rashes, respiratory tract infections, and high levels of IgE. NIAID investigators identified IL6R deficiency in 2019. Their ongoing research may help improve scientists’ understanding of drugs that inhibit the IL-6 receptor, which are often used to treat inflammatory diseases.
IL6ST deficiency is an autosomal recessive syndrome caused by mutations in the IL6ST gene that lead to infections, high IgE levels, and bone and joint abnormalities similar to those seen in STAT3 dominant-negative disease. The syndrome is also characterized by neurodevelopmental abnormalities. NIAID researchers helped identify this disorder in 2017 and continue to study it.
PGM3 deficiency is caused by autosomal recessive mutations in the gene that codes for PGM3, a protein responsible for glycosylation, which is a critical process that adds sugar molecules to proteins throughout the body. PGM3 deficiency can lead to recurrent bacterial and viral infections, autoimmunity, inflammation, severe allergic disease, developmental delays, and skeletal abnormalities. NIH researchers identified the cause of PGM3 deficiency in 2014 and continue to study the disease.
STAT3 dominant-negative disease (STAT3DN)—also known as autosomal dominant hyper-IgE syndrome (AD-HIES) or Job’s Syndrome—results from mutations in the gene that encodes a signaling protein called STAT3. This protein is involved in many different activities of the body, explaining why STAT3DN affects not only the immune system but also facial appearance, bones, lungs, skin, and arteries. NIAID investigators identified the role of STAT3 in this disease in 2007. Read more about this syndrome.
To learn more about autosomal dominant and autosomal recessive inheritance patterns, see Primary Immune Deficiency Disease Genetics and Inheritance.