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Hyper IgE Syndrome

What is Hyper IgE Syndrome?

Hyper IgE Syndrome is an atypical immunodeficiency disorder. In this condition, high serum IgE level causes multiple recurrent conditions, including, skin eruption, eczema, infections in lungs, eosinophilia^1,2.

Classification

Hyper IgE Syndrome is classified into two types:

Autosomal dominant (AD, or type 1) Hyper IgE Syndrome
Dutosomal recessive (AR, or type 2) Hyper IgE Syndrome

Both the types have overlapping clinical and laboratory manifestations but also exhibit distinct clinical features, mechanisms, and outcomes^1,3.

Autosomal Dominant

In Autosomal Dominant Hyper IgE Syndrome, the deficiency of STAT3 causes abnormal genetic mutation. This condition is first described by Davis and colleagues as Job’s syndrome in 1966. They discovered this syndrome in two girls, who had multiple episodes of pneumonia, recurrent eczema, and skin boils without the interference of hot weather. Buckley and colleagues findings referred to redefine this condition in 1972. They discovered extremely elevated IgE levels is responsible for recurrent infections, eczema, skin boils with a distinct facial appearance. From then it has been considered that immune dysfunction is the major cause of the onset of this condition. But in 2007, medical researchers found that erratic STAT3 mutations are responsible for this immunodeficiency⁴.

Autosomal Recessive

In Autosomal Recessive Hyper IgE Syndrome, erratic STAT3 mutations is not a responsible factor, as STAT3 deficiency is not found in this type of Hyper IgE Syndrome. But serum level of IgE is much higher than Autosomal Dominant type. In some patients with Autosomal Recessive Hyper IgE Syndrome has a Tyk2 deficiency, but most of the patients have normal STAT3 and Tyk2 sequences⁴.

Symptoms

Hyper IgE Syndrome Symptoms is not uniform for every case. In Hyper IgE Syndrome, immune system, skeletal system, connective tissues and teeth formation greatly affected. Some of the symptoms appear as congenital deformity, others gradually visible with increasing age. Usually, all the symptoms are apparent till adulthood of the affected individual. Therefore, diagnosis is difficult at an early stage of the disease.
Immunodeficiency disorder is a primary impairment associated with Hyper IgE Syndrome. This causes weak defensive mechanism and resultant of this leads to the frequent incidence of infections.
In some affected individuals, certain white blood cells like the number of eosinophils increased. This condition is termed as eosinophilia.
The susceptibility of the skin infection and lung infection is maximum in affected individuals due to lack of interferon gamma and interleukin-17. These two proteins are produced in the body to assist in the defensive mechanism. Decreased production of the interferon gamma and interleukin-17 proteins causes recurrent episode of skin and lung infections.
At the time of birth or during infancy, Hyper IgE Syndrome affected people have dry and itchy skin, which leads eczema and pruritis. In addition, affected infants also have “cold” abscesses, which appears as pus-filled abscesses and boils. Because Hyper IgE Syndrome affected infants do not get sufficient normal warmth.
Abscesses also develop at certain bones like mastoid bone present behind the ear, joints, gums, bronchi and lungs.
A persistent cough, sinusitis (infection of the sinuses), recurrent otitis media (middle ear infections) are also common in Hyper IgE Syndrome affected infants.
Individuals with Hyper IgE Syndrome suffering from recurrent lung infections, such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae mediated pneumonia. Chronic pneumonia can ultimately lead to pneumatoceles, in which lungs have air-filled cavities. Pseudomonas aeruginosa bacteria and Aspergillus fumigatus fungi cause pneumatoceles.
Other common infections are mediated by a yeast infection, known as mucocutaneous candidiasis and causes oral thrush (infection in mucous membranes of the oral cavity); onychomycosis (infection in nail beds); scalp, skin, and vagina also get affected with mucocutaneous candidiasis infections.
Scoliosis (side-to-side curvature of the spine), joint hyperextensibility (certain joints have increased flexibility), osteoporosis (porous bony structures due to protein loss). The resultant of this cause frequent fracture after a minor trauma.
Facial abnormalities include wide nasal bridge, elevated forehead, eyes are deep-seated, checks bones are arranged irregularly, skin abnormally hardens. Other rare abnormalities are cranial sutures present between certain bones of the skulls joints are prematurely closed. Undeveloped one-sided thoracic vertebrae, an extremely domed shaped palate. Delayed shed of primary (baby) teeth causes a late eruption of permanent teeth or sometimes causes double lined of teeth.
Some distinct eye abnormalities include chalazia means cysts or masses on the eyelid; strabismus or crossed eyes etc.
Patients suffering from Hyper IgE Syndrome also has a greater risk of cancers than the normal individuals.

In both types of Hyper IgE Syndrome has the almost similar type of symptoms. But in an autosomal recessive Hyper IgE Syndrome, patients have more serious eczema or skin abnormality than the autosomal dominant Hyper IgE Syndrome^3,4.

Causes

Autosomal Dominant Hyper IgE Syndrome is an abnormal genetic mutation occur due to inherited transmission of an abnormal gene from either parent. In each pregnancy, the risk of transmitting abnormal gene from affected parent to their offspring is 50 percent.

Study findings reported that abnormal STAT3 gene mutation causes dysfunction of STAT3 protein, resulting of this leads to defective host defense. In normal condition, STAT3 protein is synthesized in the body and involve in immune system signaling against pathogens. In Autosomal Dominant Hyper IgE Syndrome, the production of STAT3 protein is not hampered, but unable to function properly. Therefore, immune system signaling against pathogens are restricted and effortlessly pathogenic infection spread in the body^3,5.

Diagnosis

The diagnosis of Hyper IgE Syndrome is usually based on analyzing the clinical evaluation.
In the laboratory, through blood test elevation of IgE levels and certain white blood cells, including eosinophils also indicates Hyper IgE Syndrome.
Imaging tools like CT scan of lungs can detect lungs infections and the progression of pneumatoceles. The presence of pneumatoceles in lungs is considered as a marker of Hyper IgE Syndrome.
A genetic test can reveal STAT3 mutation and confirm autosomal dominant Hyper IgE Syndrome^3,5.

Treatment

Advancement of medical science recently discovered specific therapies for the STAT3 deficiency. But the treatment of both type of Hyper IgE Syndrome is based on supportive care.

Prophylactic antimicrobial therapy assists in preventing skin and lung infections mediated through different microorganisms.
Drug selection depends upon the nature of the microbial infection; such as trimethoprim-sulfamethoxazole is an effective antibiotic effective against S. aureus .
Steroid drugs can be applied topically or systemically in the case of severe eczema.
Bronchoscopy is recommended for clearing the pus or accumulated mucous from the lungs.
Immunomodulators are also prescribed for some cases to improve the immune system.
Antihelminthic drugs like Levamisole suggested improving the functioning of T cell and NK cell.
Sometimes Interferon-gamma is administered through systemic route to improve patient’s immune system, however, mixed result obtained.
Bisphosphonates are also prescribed to improve bone mineral density.
The dental procedure requires to proper settings of teeth^3,4.

Life Expectancy

An individual with Hyper IgE Syndrome usually has shorter life expectancy. Hyper IgE Syndrome affected patients usually survive till their mid- adulthood. Very rarely patient can survive till their 6 decades of life. Most of the patients die within 20 to 30 years of age due to pneumatoceles. Other possible complications like coronary heart disease, brain hemorrhage lymphomas and other types of cancer lead to the death of the patients with Hyper IgE Syndrome¹.

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References

Hyper IgE Syndrome; Immune Deficiency Foundation; http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/hyper-ige-syndrome/
Harumi Jyonouchi, (2015); Hyperimmunoglobulinemia E (Job) Syndrome; Medscape; http://emedicine.medscape.com/article/886988-overview
Hyper IgE Syndrome; Genetic And Rare Diseases Information Center; https://rarediseases.info.nih.gov/diseases/10956/hyper-ige-syndrome
Alexandra F Freeman, Steven M Holland; The Hyper IgE Syndromes; Immunol Allergy Clin North Am. Author manuscript; available in PMC 2009 May 17. Published in final edited form as: Immunol Allergy Clin North Am. 2008 May; 28(2): 277–viii. doi: 10.1016/j.iac.2008.01.005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683262/
Autosomal Dominant Hyper IgE Syndrome; National Organization For Rare Disorder; https://rarediseases.org/rare-diseases/autosomal-dominant-hyper-ige-syndrome/