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Copyright 2007, 2008, 2012
NORD is very grateful to 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 as an autosomal dominant trait and one as an autosomal recessive trait. 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 case to case. 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 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. 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 normal surrounding warmth and redness. 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 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 a yeast infection 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 often 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.
AD-HIES is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Most cases of AD-HIES occur as the result of a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Researchers have discovered that 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 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.
Symptoms of the following disorders can be similar to those of AD-HIES. Comparisons may be useful for a differential diagnosis.
Autosomal recessive hyper IgE syndrome (AR-HIES) is a rare primary immunodeficiency disorder. As with AD-HIES, affected individuals are susceptible to bacterial infections of the skin and lungs. Unlike AD-HIES, affected individuals do not have skeletal or connective tissue abnormalities or characteristic facial features, but they are much more likely to develop serious central nervous system and vascular abnormalities. In addition the types of infection that occur also differ as individuals with AR-HIES often develop viral infections (such as severe chicken pox and warts. The specific immunological defects associated with the two disorders also differ. AR-HIES more often occurs at a younger age than AD-HIES and is often more severe. AR-HIES is inherited as an autosomal recessive trait. (For more information on this disorder, choose "autosomal recessive hyper-IgE" as your search term in the Rare Disease Database.)
Atopic dermatitis is a chronic (long-lasting) disease that affects the skin. Dermatitis means inflammation of the skin and atopic refers to a group of diseases that are hereditary and often occur together. In atopic dermatitis, the skin becomes extremely itchy and inflamed causing redness, swelling, cracking, weeping, crusting, and scaling. Atopic dermatitis most often affects infants and young children, but it can continue into adulthood or first show up later in life. In most cases, there are periods of time when the disease is worse, called exacerbations or flares, followed by periods when the skin improves or clears up entirely, called remissions. Many children with atopic dermatitis will experience a permanent remission of the disease when they get older, although their skin often remains dry and easily irritated. Environmental factors can bring on symptoms of atopic dermatitis at any time in the lives of individuals who have inherited the atopic disease trait. Atopic dermatitis is often referred to as eczema, which is a general term for the many types of dermatitis. Atopic dermatitis is the most common of the many types of eczema. The cause of atopic dermatitis is unknown, although malfunction of the immune system plays a role. (For more information on this disorder, choose "atopic dermatitis" as your search term in the Rare Disease Database.)
Wiskott-Aldrich syndrome (WAS) is a rare, inherited disorder of the immune system characterized by recurrent infections due to defects in the immune system (i.e., partial defects in T lymphocyte and B lymphocyte systems, referred to as combined immunodeficiency). In addition, there is a lack of platelets (thrombocytopenia) and these patients suffer from scaly, itchy skin rashes (eczema) that vary in severity among affected individuals. Individuals with WAS carry a high risk of future development of leukemia or lymph node tumors (lymphoma). Because Wiskott-Aldrich syndrome is inherited as an X-linked recessive genetic trait, the disorder is usually fully expressed in males only. However, several reports of WAS affecting females are in the medical literature. (For more information on this disorder, choose "Wiskott-Aldrich" as your search term in the Rare Disease Database.)
Netherton syndrome is a rare hereditary disorder characterized by scaling skin, hair anomalies, increased susceptibility to atopic eczema (a skin condition that can result in dry, red and flaky skin), elevated immunoglobulin E (IgE) levels, and other related symptoms. The hair is often fragile and sparse due to a structural defect of the hair shafts that results in a ball-in-socket or bamboo stick-like appearance (trichorrhexis invaginata, "bamboo hair"). Another characteristic associated with some cases is the predisposition to allergies such as asthma, or food allergies that cause skin eruptions. Netherton syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Netherton" as your search term in the Rare Disease Database.)
A diagnosis of AD-HIES is made based upon a thorough clinical evaluation, especially a detailed patient history and identification of characteristic findings. 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) might 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. 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 may European countries) or cotrimoxazole. In severe infections, recombinant interferon g 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 may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
A variety of treatments are under investigation for the treatment of individuals with AD-HIES including cyclosporine A, immunoglobulin supplementation, or interferons. 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 Nijmegen Medical Centre
Nijmegen, The Netherlands
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Report last updated: 2012/03/06 00:00:00 GMT+0