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Hyper IgE syndrome

Hyper IgE syndromes (HIES) are rare forms of primary immunodeficiencies (PI) characterized by recurrent eczema, skin abscesses, lung infections, eosinophilia (high numbers of eosinophils in the blood), and high serum levels of immunoglobulin E (IgE). 


Table 20:1 Forms of HIES
Table 20:1 Forms of HIES (click table to enlarge).

Hyper IgE Syndromes (HIES) are rare forms of primary immunodeficiencies (PI) characterized by recurrent eczema, skin abscesses, lung infections, eosinophilia (high numbers of eosinophils in the blood), and high serum levels of immunoglobulin E (IgE). Although initially described as two forms, with autosomal dominant and autosomal recessive inheritance, we now recognize that these are two distinct disorders caused by different genetic causes. The two most common forms result from variants in STAT3, causing loss of function (STAT3-LOF), and DOCK8. These disorders share overlapping clinical and laboratory features; however, they also exhibit distinct clinical symptoms, disease courses, and outcomes. In addition, several other genetic variants have since been described to present with similar symptoms.

STAT3-LOF was described first as Job syndrome in 1966 in two girls with many episodes of pneumonia, eczema-like rashes, and recurrent skin boils. These boils were remarkable for their lack of surrounding warmth, redness, or tenderness, and were so-called cold abscesses. In 1972, the syndrome was refined and clarified. Similar infectious problems were found in two boys who also had a distinctive facial appearance and extremely elevated IgE levels. Following this report, elevated IgE was found in the two girls from the initial report, showing that Job syndrome and Buckley syndrome represented the same condition. In 2007, a heterozygous mutation in the gene encoding the transcription factor STAT3 was found to underlie most cases of autosomal dominant HIES. In 2009, variants and deletions in the DOCK8 gene were found to underlie many patients with similar symptoms inherited in an autosomal recessive fashion. 

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Clinical presentation 

STAT3 deficiency is associated with heterozygous loss of function variants in the transcription factor STAT3. This is the more common form of HIES in the U.S. It commonly presents with skin findings, including newborn rash, eczema, and recurrent staphylococcal skin abscesses, as well as ear, sinus, and lung infections. The lung infections often result in cavitary lesions in the lungs (pneumatoceles). 

Other common infections in STAT3 deficiency include mucocutaneous candidiasis (Candida fungus on mucous membranes and/or skin), manifesting typically as thrush, vaginal candidiasis, or candidal nail infection (onychomycosis), and recurrent shingles outbreaks. Additional findings include connective tissue and skeletal abnormalities, such as a typical facial appearance, hyper-extensibility of joints, retained primary teeth, recurrent bone fractures with minimal trauma, and a propensity to aneurysm formation of brain and cardiac blood vessels. Severe allergic diseases, such as food allergies, are not common in individuals with STAT3 deficiency. However, they often have positive skin prick tests making it appear that they have significant allergies.

A newborn rash or eczema is frequently the first manifestation of STAT3 deficiency. Pustular and eczema-like rashes usually begin within the first month of life, first affecting the face and scalp. Skin abscesses are a classic finding in this disorder, caused by a particular susceptibility to infections with Staphylococcus aureus. The degree of inflammatory symptoms, such as tenderness and warmth, often is quite variable. The term 'cold abscesses' is applied to those lesions that lack external signs of inflammation despite the presence of pus. The occurrence and severity of these abscesses substantially decrease with prophylactic therapy with antibiotics against Staphylococcus aureus. Deep tissue abscesses, such as liver or bone infections, are much less common in AD-HIES.

Recurrent bacterial cases of pneumonia are often encountered in individuals with AD-HIES. Pneumonias typically start in childhood and are most frequently caused by Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Similar to the occurrence of cold skin abscesses, these types of pneumonia may present with fewer symptoms than would be expected in a person with intact immunity. This relative lack of symptoms and subsequent delay in clinical presentation may contribute to advanced disease and significant tissue damage before identification and initiation of appropriate therapy. 

Infection-induced tissue destruction in individuals with AD-HIES may give rise to pneumatocele formation, and large cavities in the lung, which is a distinguishing feature of AD-HIES due to STAT3 deficiency. When pneumatoceles or bronchiectasis are present in the lungs, the individuals are more susceptible to lung infections with other bacteria, such as Pseudomonas, and molds, such as Aspergillus.

The involvement of both the connective and skeletal tissues is an important feature of STAT3 deficiency. An asymmetrical facial appearance with a prominent forehead and chin, deep-set eyes, broad nose, thickened facial skin, and a high-arched palate are typical of this disorder. These features evolve during childhood and become more established by adolescence. 

Individuals with AD-HIES also exhibit hyperextensibility of the joints. They frequently suffer bone fractures from seemingly insignificant trauma and bone density may be reduced. Scoliosis is common and typically emerges during adolescence or later in life. Craniosynostosis (fused skull bones) and extra or abnormally formed ribs or vertebrae are also found more often in those with AD-HIES than in the general population. These skeletal abnormalities are not usually seen in individuals with DOCK8 deficiency.

Abnormalities affecting the teeth are another common feature of AD-HIES with STAT3 mutations. Retention of primary teeth, even after the permanent teeth have erupted, is a consistent finding. This abnormality is revealed on panoramic x-ray views as double rows of retained primary teeth overlaying the permanent ones. Surgical extraction of the retained primary teeth is often necessary for healthy dentition. Children who have had their retained primary teeth extracted will have a normal eruption of their permanent teeth. 

Individuals with AR-HIES due to DOCK8 deficiency have characteristics similar to STAT3 deficiency such as eczema, skin abscesses caused by Staphylococcus aureus, recurrent respiratory infections, mucocutaneous candidiasis, and other fungal infections. However, those with DOCK8 deficiency are distinguished from those with AD-HIES by the lack of joint, bone, and teeth changes. They tend to have frequent occurrences of severe, recurrent viral infections not seen in those individuals with STAT3-LOF. Individuals with DOCK8 deficiency often have frequent outbreaks caused by herpes simplex virus (cold sores or other skin lesions), herpes zoster virus (shingles), human papillomavirus (HPV; difficult-to-treat warts), and molluscum contagiosum, a viral skin infection that causes round, firm, painless bumps that can occur on any part of the body.

Recurrent lung infections are common in DOCK8 deficiency, and they may also lead to chronic lung disease with damage to the airways (bronchiectasis) and lung tissues. However, cavitary lesions are not commonly seen in DOCK8 deficiency. DOCK8 deficiency is also associated with a higher incidence of pneumonia caused by the fungus Pneumocystis jirovecii. Liver disease can result from chronic infection with the parasite Cryptosporidia.

Asthma and allergies can be more severe in DOCK8 deficiency, including food allergies manifesting with anaphylaxis.

Vasculitis (inflammation within blood vessels) may occur in the brain blood vessels and in the main body vessels, such as the aorta. This may lead to a stroke, resulting in neurologic impairments. 

Risk of cancer

Both individuals with STAT3-LOF and DOCK8 deficiency are at increased risk for cancer, especially lymphoma. Individuals with DOCK8 deficiency are susceptible to papillomavirus-induced squamous cell carcinoma as well as lymphomas, particularly Epstein-Barr virus (EBV)-induced lymphoma. 

Laboratory findings

Both STAT3 and DOCK8 deficiency impact the immune system and lead to immunological abnormalities. Increased serum IgE concentrations and eosinophil numbers are present in both forms of HIES.

In those with STAT 3 deficiency, total white blood cell counts are typically normal and may not increase appropriately during acute infection. Neutropenia (low numbers of white blood cells called neutrophils) is seen in some people but is not severe. A special type of T cell called Th17 cells is very low. Antibody levels, including IgG, IgA, and IgM levels, are usually normal, but the ability to respond to vaccines is sometimes abnormal. Some may require immunoglobulin (Ig) replacement therapy.

Individuals with DOCK8 deficiency typically have low numbers of T cells, which often decrease further with age. They also tend to have low serum IgM levels, and vaccine antibody responses are often poor. 

Diagnosing hyper IgE syndromes

The diagnosis of HIES can be made based on a combination of clinical and laboratory findings for both AD- and AR-HIES. An elevated level of serum IgE is a virtually universal finding in these individuals. However, it is not sufficient on its own to make the diagnosis, as people with other conditions, such as severe eczema, may also have very high IgE levels.

An HIES scoring system has been previously developed at the National Institutes of Health (NIH) that can help diagnose STAT3-LOF. In this system, individuals are evaluated for the existence and severity of the following clinical and laboratory features: newborn rash, eczema, skin abscesses, recurrent upper respiratory infections, pneumonia, lung cavities, candidiasis, other severe infections, fatal infections, characteristic facial appearance, increased nasal width, high palate, retained primary dentition, joint hyper-extensibility, fractures with minor trauma, scoliosis, midline anatomic abnormalities, lymphoma, high serum IgE level, and eosinophilia. The score correlates with the presence of the disease, and higher scores reflect a more severe presentation. In addition, another study demonstrated that scoring five features: eosinophilia, parenchymal lung disease, frequency of sinusitis/ otitis, retained primary teeth, and minimal trauma fractures allowed differentiation between STAT3-LOF versus DOCK8 deficiency.

A definitive diagnosis can be established with genetic analysis of the STAT3 and/or DOCK8 genes.


STAT3 deficiency

STAT3-LOF occurs in both males and females of all ethnic groups with apparently equal frequency. In many, the disorder occurs sporadically but then can be passed down to children in an autosomal dominant manner, with each child having a 50% chance of having the variant. Variant analysis of the STAT3 gene enables definitive diagnosis and genetic counseling.

DOCK8 deficiency

Some individuals with AR-HIES are from families that are consanguineous, where parents are related or descended from the same ancestor. Deletions and variants occur in the DOCK8 gene on chromosome 9. Mutational analysis of the DOCK8 gene is important for diagnosis and genetic counseling. 


Antibiotic prophylaxis with trimethoprimsulfamethoxasole is frequently used as prevention against recurrent respiratory infections and staphylococcal abscesses. Treatment for these infections, when they occur, should be started promptly.

Given that most individuals with HIES suffer from significant eczema and skin infections from having open lesions on the skin, skincare and prompt treatment of skin infections is an important component of HIES management. When the eczema is severe, topical moisturizing creams, non-steroidal topical creams, and limited use of topical steroids can help achieve healing. Cleaning the skin by bathing with chlorhexidine or dilute bleach baths helps to reduce the amount of bacteria on the skin. Skin abscesses may require incision and drainage but can largely be prevented with prophylactic oral antibiotics.

A remarkable feature of STAT3 deficiency is how well the individuals may feel (and appear) when they have an infection. For example, even with evidence of a significant infection on physical examination and X-ray corroboration of pneumonia, the individual may deny feeling sick and may not feel the need for invasive diagnostic testing or prolonged therapy. Moreover, doctors unfamiliar with the diagnosis can be hesitant to believe that individuals who do not appear very ill can really be quite sick. Therefore, it is always important for individuals with this diagnosis to see their healthcare providers when there are even mild symptoms. Lung infections need to be diagnosed and treated promptly to prevent the formation of pulmonary cavities. Once lung cavities are present, antifungal prophylaxis is often recommended to prevent mold infections. In those with structural lung disease, pulmonology consultation is recommended to assist with the development of a regimen to improve airway clearance and decrease the risk of further damage.

Frequent candidiasis of the fingernails, mouth, or vagina may lead to consideration of antifungal prophylaxis. Also, individuals with this disorder are more susceptible to some environmental fungi that are more common in certain parts of the country, such as Histoplasmosis and Coccidiodes. Discussing with your healthcare provider any precautions based on location is important.

Those with DOCK8 deficiency with herpes infections or shingles may benefit from prophylaxis with an antiviral agent such as acyclovir. Since those with DOCK8 deficiency have a higher incidence of Pneumocystis jirovecii, pneumonia prophylaxis for this disease is often recommended. These individuals are also more susceptible to the parasite Cryptosporidia, which can be found in water. Depending on the water supply, bottled or filtered water may be recommended. Individuals with this diagnosis may be counseled to avoid water parks and swimming in freshwater lakes, ponds, or rivers.

Hematopoietic stem cell transplantation (HSCT) is generally recommended for people with DOCK8 deficiency, given the severity of the disease and the risk of developing fatal complications, including infections and malignancies, early in life. In STAT3 deficiency, the role of HSCT is less clear, but it has been effective in select individuals with severe disease symptoms early in life.

In individuals with STAT3 deficiency who have demonstrated fractures, using a DEXA scan and consultation with an endocrinologist focused on bone health is recommended. Calcium and vitamin D supplementation can also be considered. Collaboration with a dentist is essential in children to determine the optimal age to remove baby teeth. Adults should be monitored for high blood pressure as well as heart and brain aneurysms.


Individuals with both types of HIES require constant vigilance with regard to infections and the development of chronic lung disease.

With early diagnosis and treatment of infections, most individuals with STAT3 deficiency do fairly well. DOCK8 deficiency is associated with a much higher risk of death by age 30 without HSCT. The more severe nature of DOCK8 deficiency should prompt early consideration of HSCT.

Genetic counseling is advised for families with HIES children and is especially important for those families where consanguinity is involved.

Organizations supporting patients and familes with hyper IgE syndrome

Job Research Foundation

fleur de lis in blue with organization title

Funds research into Job syndrome with the hope of finding better therapies and treatments for those living with the disease.

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA