Hyperimmunoglobulin E syndrome

Overview

Hyperimmunoglobulin E syndrome (HIES), also known as Job's syndrome, is a rare primary immunodeficiency disorder characterized by extremely elevated levels of immunoglobulin E (IgE), recurrent skin and lung infections, and eczema-like rashes. The condition may also include connective tissue and skeletal abnormalities. There are two main forms of HIES: autosomal dominant (AD-HIES) and autosomal recessive (AR-HIES), each associated with different genetic mutations and clinical features.

Causes

HIES is caused by mutations that impair immune system function. The two primary genetic causes are:

• Autosomal dominant HIES (AD-HIES): Caused by mutations in the STAT3 gene. This form is also associated with skeletal and connective tissue abnormalities.

• Autosomal recessive HIES (AR-HIES): Often caused by mutations in the DOCK8 gene. This form is typically more severe, with increased risk of viral infections and certain cancers, but without skeletal abnormalities.

These mutations lead to impaired signaling in immune cells, resulting in defective responses to infections and abnormal regulation of IgE production.

Symptoms

Symptoms of Hyper-IgE syndrome often begin in infancy or early childhood and may include:

• Extremely high serum IgE levels

• Recurrent skin abscesses and boils, often without redness or pain ("cold abscesses")

• Chronic eczema or eczema-like rash

• Recurrent lung infections (e.g., pneumonia), which may lead to lung damage and formation of pneumatoceles

• Frequent sinus and ear infections

• Delayed shedding of baby teeth

• Scoliosis, joint hyperextensibility, or other skeletal abnormalities (especially in AD-HIES)

• Frequent viral infections, particularly in AR-HIES

Patients may also have a characteristic facial appearance, including a broad nasal bridge and deep-set eyes, particularly in AD-HIES.

Diagnosis

Diagnosis of HIES involves clinical evaluation, laboratory testing, and genetic confirmation. The diagnostic process includes:

• Serum IgE testing: IgE levels are typically >2,000 IU/mL, though levels can fluctuate

• Complete blood count: May show eosinophilia (high levels of eosinophils)

• History of recurrent infections and characteristic clinical features

• Genetic testing: Identification of mutations in STAT3 or DOCK8 confirms the diagnosis and helps distinguish between AD-HIES and AR-HIES

• Imaging studies: To assess lung damage or skeletal abnormalities

Early diagnosis is crucial for proper management and prevention of complications.

Treatment

There is no cure for Hyper-IgE syndrome, but treatment focuses on managing infections and minimizing complications. Treatment strategies include:

• Prophylactic antibiotics: To prevent recurrent bacterial infections

• Antifungal and antiviral medications: Especially in AR-HIES, where viral infections are more common

• Skin care: Regular skin hygiene and topical treatments to manage eczema and prevent skin infections

• Immunoglobulin replacement therapy: May be used in some patients with antibody deficiencies

• Hematopoietic stem cell transplantation (HSCT): Can be curative in DOCK8-deficient AR-HIES but is not typically used for AD-HIES

Multidisciplinary care involving immunologists, dermatologists, pulmonologists, and infectious disease specialists is often required.

Prognosis

The prognosis for individuals with HIES depends on the subtype and severity of the disease. Patients with AD-HIES can often live into adulthood with careful management of infections and complications. AR-HIES is generally more severe, with a higher risk of viral infections, malignancies, and early mortality without stem cell transplantation. Lifelong monitoring and preventive care are essential to improve outcomes and maintain quality of life.