Autosomal Dominant Hyper IgE Syndrome

Autosomal dominant hyper IgE syndrome (AD-HIES) is a rare multisystem primary immunodeficiency disorder distinguished by the clinical triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections. 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 their different expressions of the same disorder, but now researchers consider them similar, yet distinct disorders.

Causes

Mutations in the STAT3 gene cause AD-HIES. The STAT3 gene is responsible for the 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.

Related Disorders

Symptoms of the following disorders can be similar to those of AD-HIES. Comparisons may be useful for a differential diagnosis.

Recently, a clinical disorder closely resembling AD-HIES was described which appeared to be due to an autosomal recessive mode of inheritance of mutations in the ZNF341 gene. ZNF341 was demonstrated to regulate the function of STAT3.

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 and recurrent chickenpox 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. 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 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. Of note, the IgE levels in the blood are often elevated in atopic dermatitis (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 carried 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), and 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.

Symptoms

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 in 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 infections, 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), and 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).

Immunologic Characteristics

Recurrent skin and sinopulmonary infections are noted in early childhood.

Recurrent staphylococcal boils usually manifest in the first few years of life and may be “cold,” lacking the cardinal features of inflammation, warmth, redness, and pain.
Recurrent cases of pneumonia begin as well in the first few years, with the most common bacterial isolates being Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Abnormal healing of this pneumonia frequently leads to pneumatoceles and bronchiectasis.
Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
Opportunistic infections include Pneumocystis jiroveci pneumonia, disseminated histoplasmosis and Cryptococcus, and secondary infection of the pneumatoceles with molds such as Aspergillus fumigatus or Scedosporium species may occur. Histoplasmosis most frequently disseminates to the intestinal tract and can mimic inflammatory bowel disease. Coccidioides and Cryptococcus have caused meningitis [rx].
Decreased central memory T-cells may lead to increased incidence of varicella-zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [rx].

Nonimmunologic Characteristics

Individuals with STAT3–HIES may have several additional nonimmunologic findings.

Facial. A characteristic facial appearance including facial asymmetry, deeply set eyes, a broad nose, and prominent skin pores typically emerges by adolescence [rx, rx].

Oral findings include a high arched palate and oral mucosal variants including prominent palatine ridges [rx]. Failure of primary teeth exfoliation is common; secondary tooth development is normal if the primary teeth are removed.

Skeletal abnormalities include osteoporosis, minimal trauma fractures, scoliosis, joint hyperextensibility, and craniosynostosis.

Osteoporosis and minimal trauma fractures start in early childhood.
Scoliosis typically develops through childhood and adolescence and may require surgical correction.
Joint hyperextensibility is common, and adults may have degenerative joint disease.
Varying degrees of craniosynostosis can be seen, although the surgical correction is rarely required. Skull radiographs often have a “beaten copper” appearance. Mild craniosynostosis is frequently noted in skull imaging.

Brain imaging reveals Chiari 1 malformations in approximately 20% of individuals and focal hyperintensities prominent on T₂-weighted images in approximately 70% of individuals.

The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [rx].

Vascular abnormalities including tortuosity of middle-sized arteries and aneurysms have been described [rx, rx]. The coronary arteries have been the most completely studied.

The combination of tortuosity and dilatation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
Clinical sequelae have been rare but include myocardial infarction.

A cerebral artery aneurysm has also been described and is infrequently associated with subarachnoid hemorrhage.

Gastrointestinal issues vary [rx]:

Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
Upper endoscopy frequently shows eosinophilic esophagitis.
Diverticula can occur at a relatively young age and may be associated with bowel perforation [rx].
Spontaneous intestinal perforations have also been described.
Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).

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.

Diagnosis

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.

History

Patients of hyper IgE syndrome are born with pustular or eczematoid rashes, or they may appear in the first month of life.^[rx]
Recurrent eczema, boils, and skin abscesses.
Recurrent infections such as chronic otitis media, sinusitis, pneumonia, mucocutaneous infections, and neurological and systemic.
Hyperextensible joints/recurrent bone fractures, and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide internal distance) in early childhood.
Eczema is complicated by mucocutaneous candidiasis involving the mouth and diaper areas.
Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyperextensibility, and degenerative joint disease.
Retained primary teeth past the age of normal dental exfoliation.

Physical Examination

Coarse facial features( prominent forehead, deep-set eyes, broad nasal bridge, and wide internal distance).^[22]
Dental abnormalities- retained primary teeth.
Facial pain (sinusitis), ear pain, and discharge (otitis media).
Purulent sputum producing cough or dry cough due to recurrent pneumonia.
Eczematous dermatitis and lichenification affect the face, trunk, and extremities.
Boils and multiple skin abscesses.
Purpura rash.
Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyper-extensible, and degenerative joint disease.^[rx]

Immunological Features

These mainly include chronic eczematoid eruptions, recurrent skin and pulmonary bacterial infections, and mucocutaneous candidiasis. The skin manifestations usually appear very early, a few weeks after birth. They include a pruriginous eczematoid rash affecting the scalp and face, that is rapidly superinfected with Staphylococcus aureus, resulting in weeping, crusty, and follicular infectious lesions.
Recurrent cold staphylococcal skin abscesses that are associated with little or no inflammation are seen in these patients. Candida infections are common; they affect the skin, mucous membranes, and nails.
Recurrent pneumonia is typical, predominately due to S. aureus, and less frequently due to Streptococcus pneumoniae, and Haemophilus. It can get complicated with the development of recurrent lung abscesses, bronchiectasis, and pneumatoceles. These pneumatoceles can get colonized with Aspergillus and Pseudomonas. Superinfection with Pneumocystis carinii[rx] was also reported.
Cryptococcosis and histoplasmosis can manifest outside the lung. Other infectious manifestations such as sinusitis, bronchitis, otitis externa, gingivitis, dental abscess, septic arthritis, and osteomyelitis can be seen.[rx][rx][rx][rx][rx]

Non-immunological Features

Patients with Job syndrome have characteristic facial features that appear in early adolescence or earlier in late childhood, for example, facial asymmetry, prominent forehead, deep-set eyes, broad nasal bridge, wide fleshy nasal tip[rx], rough fascial skin, increased inter-alar distance, prognathism, and high-arched palate. Birth defects like craniosynostosis and Arnold Chiari type 1 malformation have been documented.
Musculoskeletal abnormalities are common. They include hyperextensibility of the joints, scoliosis, and osteopenia. Hyperextensibility(noted in about 68% of the patients) may result in the early onset of degenerative joint disease. Bone density is decreased and is the source of multiple pathological fractures that occur in approximately 50% of patients (long bones and ribs). Scoliosis of variable severity is observed in approximately 60% of patients.
Anomalies of dentinogenesis are possible manifestations. Decreased resorption of the roots of the deciduous teeth may result in prolonged retention of the deciduous teeth, preventing the appearance of definitive teeth. About 70% of the patients with Job syndrome have been reported to retain three or more primary teeth.
Vascular manifestations include tortuosity or dilatation, coronary, cerebral and aortic aneurysms, and congenital coronary artery abnormalities. Ocular complications include xanthelasmas, chalazion, strabismus, and retinal detachment.
The main diagnostic feature is an increase in serum IgE levels of more than 2000 U/mL, and often 500 U/mL. A clinical score has been developed to define the probability of diagnosis. A total IgE concentration greater than 1000 IU/mL and a weighted score of greater than 30 indicate an AD-HIES of the defect in STAT3, and a dominant-negative heterozygote mutation in STAT3 confirms the diagnosis.[rx][rx]
Eosinophilia is observed in more than 90% of the patients. The WBC count can be normal, elevated, or reduced in number(neutropenia).[rx]
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 confirm the diagnosis in some 60% of cases. Hence, the absence of such a mutation does not rule out the diagnosis of AD-HIES.

Treatment

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 the 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.

Treatment of hyper IgE syndrome includes prevention of infections, administering prohphylactic antibiotics, treating current infections and bone marrow transplant.

Skin care with antiseptic wash prevents infection with bacteria and fungi.
- Eczematous dermatitis is treated with a topical corticosteroid, a moisturizing cream, and an antihistamine .
Prophylactic administration of trimethoprim-sulfamethoxazole is useful in the prevention of cutaneous staphylococcal infections, including abscesses, as well as sinusitis, otitis media, and pneumonia.
- 5 to 8 mg/kg/day of the trimethoprim component administered orally in two divided daily doses, or from 0 to 6 months, 120 mg/day; 6 months to 5 years, 240 mg/day; 6 to 12 years, 480 mg/day; and >12 years, 960 mg/day.
Treatment of active infections:
- Pneumonia and deep-seated abscesses caused by S aureus are treated intravenously with nafcillin and with vancomycin if it is methicillin-resistant.
- Lung abscesses superinfected with Aspergillus species require intravenous amphotericin B.
- P aeruginosa, requires an aminoglycoside and a third-generation cephalosporin or another synergistic antibiotic.
Bone marrow transplantation (BMT) is also being studied to be used for treatment.

Surgery

Surgery is not recommended for the treatment of hyper IgE syndrome.

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. Another treatment is symptomatic and supportive.

Autosomal Dominant Hyper IgE Syndrome

Causes