September 06, 2018
Years published: 2007, 2008, 2012, 2015, 2018
NORD gratefully acknowledges Jos W.M. van der Meer, MD, PhD, FRCP Lon, FRCP Edin, Professor of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, for assistance in the preparation of this report.
Autosomal dominant hyper IgE syndrome (AD-HIES) is a rare multisystem primary immunodeficiency disorder. Symptoms often become apparent early during infancy or childhood. The disorder is characterized by repeated bacterial infections of the skin and lungs (pneumonia), skeletal abnormalities, and characteristic facial features. The first symptom is often the development of a dry, red flaky skin rash (eczema) at birth or early during infancy. Researchers have discovered that mutations in the STAT3 gene cause AD-HIES in over 60% of the patients. Most cases of AD-HIES occur as the result of a new mutation in this gene. There are two main forms of hyper IgE syndrome – one inherited in an autosomal dominant pattern and one in an autosomal recessive pattern. Both involve defects of the immune system and elevated levels of immunoglobulin E (hyper IgE) in the blood. For years, researchers considered them different expressions of the same disorder, but now researchers consider them similar, yet distinct disorders.
The symptoms of AD-HIES may vary greatly from person to person. AD-HIES affects the immune system as well as the development of the skeleton, connective tissue, and teeth. Symptoms may become apparent at birth, during infancy, or during early childhood. In some cases, symptoms may not become apparent until adulthood, and it is not uncommon that the diagnosis is made late.
AD-HIES is a rare primary immunodeficiency disorder, one of a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms [microorganisms]). The T cell system (cell-mediated immune response) contributes to fighting several viruses, some bacteria and yeast and fungi. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g., saliva). There are five classes of immunoglobulins (Ig) known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. (The white blood cells [leukocytes] are part of the body’s system of defenses, playing an essential role in protecting against infection as well as fighting infection once it occurs.) In addition, antibodies are produced following vaccination, contributing to protection from infectious diseases like polio, measles, and tetanus.
Many individuals with AD-HIES have abnormally high levels of immunoglobulin IgE in the fluid portion of the blood (thus the term hyper IgE). Affected individuals often have somewhat elevated numbers of certain white blood cells known as eosinophils in the body (eosinophilia). The exact reasons for the susceptibility to infection are not understood but a decreased production of the defense proteins interferon gamma and interleukin-17 plays a role. These proteins are important for the attraction and activation of white blood cells to sites of infection. Individuals with AD-HIES are susceptible to recurrent episodes of certain bacterial infections that may affect the skin and lungs.
The first symptom of AD-HIES may be a dry, red flaky skin rash (eczema) that develops at birth or early during infancy. Itchiness (pruritis) may also occur. In addition, infants are particularly susceptible to bacterial infection, especially staphylococcal infections. Such infections may cause boils and pus-filled holes (abscesses) to form on the skin. These abscesses are referred to as “cold” abscesses because they lack the surrounding warmth and redness one would expect to accompany such an infection. This can be understood from the fact that few white blood cells are attracted to the site of infection. Abscesses may also be found on the bone behind the ear (mastoid), joints, gums, air passages in the lungs (bronchi), and in the lungs themselves. Affected infants may also have a persistent cough, infection of the sinuses (sinusitis), and recurrent middle ear infections (otitis media).
Individuals with AD-HIES develop recurrent lung infections (pneumonia) most often caused by the bacteria Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Pneumonia eventually leads to the development of air-filled cavities within the lungs (pneumatoceles). Pneumatoceles are especially prone to infection with bacteria such as Pseudomonas aeruginosa and especially fungi such as Aspergillus fumigatus.
Affected individuals may also be unusually susceptible to opportunistic infections. The term opportunistic infection refers either to infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. The most common opportunistic infection associated with AD-HIES is an infection caused by the yeast Candida. This is known as mucocutaneous candidiasis, which can affect the mucous membranes of the mouth (oral thrush) or the nail beds (onychomycosis). Mucocutaneous candidiasis can also affect the skin, scalp, and vagina.
Additional symptoms may occur in individuals with AD-HIES including skeletal abnormalities and distinctive facial features. Skeletal abnormalities include abnormal side-to-side curvature of the spine (scoliosis), abnormally increased flexibility of certain joints (joint hyperextensibility), progressive thinning and loss of protein of the bones (osteoporosis), and repeated fractures of the long bones of the arms and legs and the ribs. Fractures may occur after minor trauma.
Individuals with AD-HIES have characteristic facial features including a broad nasal bridge, deep-set eyes, prominent forehead, and irregularly proportioned cheeks and jaws, and generalized hardening (coarsening) of the skin. Rare facial abnormalities include premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), underdevelopment of one side of the bones in the middle (thoracic) portion of the spinal column (hemivertebrae), and a highly arched palate. Another finding in individuals with AD-HIES is the failure to shed primary (baby) teeth, which, consequently, delays the eruption of permanent teeth or leads to double rows of teeth.
Individuals with AD-HIES may also have various eye (ocular) abnormalities including the development of masses or cysts on the eyelid (chalazia), and crossed eyes (strabismus).
Some individuals have developed certain cancers (malignancies) suggesting that AD-HIES may be associated with a greater risk of developing malignancy than the general population. The most common cancers associated with AD-HIES are cancers affecting the lymphatic system (lymphomas) such as anaplastic large cell lymphoma and peripheral T-cell lymphoma.
Mutations in the STAT3 gene cause AD-HIES. The STAT3 gene is responsible for production of one of the signal transducer and activator of transcription (STAT) proteins that are involved in signaling the immune system to respond to pathogens. The mutations associated with AD-HIES result in a normal amount of STAT3 protein produced but the function of the protein is affected resulting in defective host defense.
Mutations in other genes may also be associated with AD-HIES, since STAT3 mutations are found in about 60% of patients.
AD-HIES is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
AD-HIES affects males and females in equal numbers and occurs in all ethnic groups. More than 200 cases of hyper IgE syndrome (both the dominant and recessive forms) have been described in the medical literature. However, these disorders may often go unrecognized or misdiagnosed, making it difficult to determine their true frequency in the general population. Although AD-HIES is present during infancy, diagnosis may not be made until adolescence and, in some cases, adulthood.
The first case of hyper IgE syndrome was described in the medical literature in 1966. The physicians termed the disorder Job syndrome after the biblical character of Job who was covered in boils and sores over his entire body.
A diagnosis of AD-HIES is made based upon a thorough clinical evaluation, especially a detailed patient history and identification of characteristic findings by a physician with experience with the syndrome. Laboratory studies that may aid in a diagnosis include blood tests that demonstrate elevated levels of IgE in the blood and elevated levels of certain white blood cells known as eosinophils (eosinophilia). IgE levels may drop to normal or near normal levels in adulthood and, therefore, normal IgE levels in an adult do not necessarily rule out a diagnosis of AD-HIES.
X-ray studies such as computed tomography (CT scanning) may be used to detect lung infections and the development of pneumatoceles within the lungs. Pneumatoceles are an indicator of AD-HIES. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
A scoring system was devised by researchers at the National Institutes of Health (NIH) to aid in making a diagnosis of AD-HIES. Genetic tests revealing a STAT3 mutation confirms the diagnosis in some 60% of cases. Hence, absence of such mutation does not rule out the diagnosis of AD-HIES.
The treatment of AD-HIES is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists for adults, dermatologists, dental specialists, immunologists, orthopedists, and other health care professionals may need to systematically and comprehensively plan treatment.
The mainstay for treatment of individuals with AD-HIES is preventative (prophylactic) antibiotic therapy against bacterial infection. Common antibiotic medications (e.g., anti-staphylococcal agents) used to treat individuals with AD-HIES include dicloxacillin (flucloxacillin in many European countries) or cotrimoxazole. In severe infections, recombinant interferon-gamma subcutaneously may be given as an adjunctive treatment.
Some affected individuals may require therapy for mucocutaneous candidiasis such as fluconazole or itraconazole, which are anti-fungal drugs. Surgical drainage of existing skin lesions, followed by a regimen of antibiotic therapy may be required in some cases. Topical steroids and moisturizing creams may also be used to treat skin lesions.
Chronic lung infections may lead to the formation of air cavities (pneumatoceles), which can potentially become infected with Pseudomonas aeruginosa and Aspergillus fumigatus. The drug treatment of these infections can be difficult and management may require surgically opening the chest (thoracotomy) to allow for the removal or drainage of such infected pneumatoceles.
Affected individuals may have retained primary teeth removed, be regularly monitored for the development of scoliosis, and be evaluated for fractures following even minor trauma. Scoliosis and fractures may require treatment with various orthopedic procedures.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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A variety of treatments are under investigation for the treatment of individuals with AD-HIES including cyclosporine A, immunoglobulin supplementation, antibodies directed against IgE, and interferons. There is limited experience with hematopoietic stem cell transplantation in HIES. Of these, the clinical experience with interferon-gamma given by injection for serious infectious in HIES is promising. Most of these treatments are used for individuals who are unresponsive to other forms of treatment. More research is necessary to determine the long-term safety and effectiveness of such potential therapies for individuals with AD-HIES.
Contact for additional information about autosomal dominant hyper IgE syndrome:
Jos W.M. van der Meer, MD, PhD, FRCP Lon, FRCP Edin
Professor of Medicine
Radboud University Medical Centre
Nijmegen, The Netherlands
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