OVERVIEW

What is Hyper IgE Syndrome?

Hyperimmunoglobulin E syndrome (HIES) is a hereditary immunodeficiency syndrome characterized primarily by elevated IgE levels, also known as Hyper IgE syndrome.

It is caused by defects in the signal transducer and activator of transcription-3 (STAT3) within the Janus kinase-STAT signaling pathway. There are three main clinical manifestations:

• Recurrent (cold) skin abscesses;
• Recurrent pneumonia and infections in other areas;
• Elevated IgE levels (often ≥10 times the upper limit of normal).

Treatment for this condition is challenging, primarily focusing on managing skin abscesses and controlling or preventing infections. The prognosis is poor, with most patients dying from severe infectious complications in the lungs.

Is Hyper IgE Syndrome Common?

Hyper IgE syndrome is a rare disease, and its exact prevalence is unknown. Estimates suggest 0.2 to 1 per 100,000 individuals. There is no difference in incidence between males and females, and cases have been reported in African, Asian, and Caucasian populations.

SYMPTOMS

What symptoms and signs do patients with Hyper IgE Syndrome typically exhibit?

Hyper IgE Syndrome can cause multisystem involvement:
Skin:

• Beginning in the first few weeks after birth, a papulopustular and often crusted rash appears, initially on the face and scalp, then spreading to the upper trunk/shoulders and buttocks. The rash progresses to eczematous, pustular, and intensely pruritic lesions resembling atopic dermatitis. The rash is diffusely distributed and may develop lichenification.
• Pustular lesions and other infections in these patients are "cold"-like. While typical infections cause localized warmth, the skin lesions in these patients do not exhibit increased temperature.

Respiratory infections:

• Severe infections are common, yet patients often remain afebrile and feel well.
• Chronic upper airway infections with persistent and/or recurrent sinusitis, suppurative otitis media, and mastoiditis.
• Recurrent and potentially life-threatening pulmonary infections, often complicated by structural lung abnormalities such as bronchiectasis, pulmonary cavities/bullae, lung nodules, and bronchopleural fistulas. These structural changes increase susceptibility to opportunistic infections like fungi and nontuberculous mycobacteria.

Increased susceptibility to infections:

• Most commonly caused by Staphylococcus aureus, Candida albicans, Haemophilus influenzae, group A and B streptococci, Gram-negative pathogens (e.g., Pseudomonas), and other fungi.
• S. aureus predominates in skin infections, while S. aureus and H. influenzae are common in pulmonary infections. C. albicans frequently affects the oral cavity, vagina, and nails.

Distinctive facial features:

• An unusual observation is that patients with this syndrome share more facial similarities with each other than with their own family members.
• The most characteristic features include a broad nasal base and wide nasal bridge. Other traits include a prominent forehead (frontal bossing), increased intercanthal distance, and deep-set eyes. In infancy, a protruding forehead, full lower lip, and broad nose are noticeable.
• Marked thickening of facial and auricular soft tissues gives the skin a doughy texture, often described as "coarse facies." This feature is evident in 80%–100% of patients, becomes more pronounced with age, and typically emerges between 2–5 years, peaking after puberty.

Skeletal abnormalities:

• Retention of primary teeth, leading to double rows of teeth.
• Osteoporosis, predisposing to minor fractures.
• Scoliosis and joint hyperextensibility may also occur.

Other manifestations:

• Increased risk of lymphoma.
• Neurological abnormalities, resulting in relatively poorer cognitive skills, visual-perceptual skills, and working memory.
• Congenital and acquired vascular anomalies, such as aneurysms, pseudoaneurysms, and vasculitis. Coronary artery abnormalities include tortuosity, dilation, and localized aneurysms, which may lead to severe complications or death.

CAUSES

What are the causes of hyper IgE syndrome?

Defects in the JAK-STAT pathway impair the differentiation and function of T helper 17 cells. However, the exact mechanism by which this simultaneously leads to susceptibility to infections, skin diseases, skeletal disorders, and immune diseases remains unclear.

Elevated serum IgE levels are likely a secondary abnormality rather than the core pathogenesis. Current research suggests that impaired production or regulation of interferon-γ in patients contributes to increased IgE levels.

What are the genetic characteristics of hyper IgE syndrome?

Most cases of hyper IgE syndrome follow an autosomal dominant inheritance pattern, but some may result from gene mutations, making the genetic features somewhat ambiguous.

DIAGNOSIS

What are the special laboratory abnormalities in patients with Hyper IgE Syndrome?

The most common findings are elevated serum IgE levels and peripheral blood eosinophilia.

• IgE: Typically ranges from 1,000 to 50,000 U/mL, though levels may be lower or higher. Serum IgE levels do not correlate with disease severity. In infancy, IgE levels may be extremely high. Over time, IgE levels may stabilize or decline, and some adult HIES patients may normalize their IgE levels.
• Eosinophil count: Often rises before acute infections.
• Others: Elevated total IgG, IgM, and IgA levels; normal complement; some may have increased IgD, etc.

How is Hyper IgE Syndrome diagnosed?

Many conditions can cause elevated blood IgE levels. Therefore, diagnosis relies on symptoms, signs, and laboratory tests to confirm STAT3 mutations. The more clinical features align, the more likely it is STAT3 mutation-related:

• Characteristic facial features;
• Internal organ abscesses;
• Severe infections;
• Pulmonary pneumatoceles;
• Onychomycosis and mucocutaneous candidiasis;
• Scoliosis;
• Fractures.
  Physicians must actively differentiate HIES from other conditions causing elevated IgE to minimize misdiagnosis or missed diagnosis.

What diseases should Hyper IgE Syndrome be differentiated from?

• Atopic dermatitis (eczema): Both involve intense itching and elevated IgE. However, atopic dermatitis is more likely to involve food allergies, whereas HIES commonly presents with opportunistic infections, severe infections, organ abscesses, characteristic facial features, scoliosis, and fractures.
• Dedicator of cytokinesis 8 (DOCK8) deficiency: Some classify this as another form of HIES due to clinical similarities with STAT3 mutations. Distinguishing features may include:
  • DOCK8 deficiency involves liver damage, higher malignancy rates, frequent upper respiratory infections, viral skin infections, and more pronounced eosinophilia. It resembles atopic dermatitis and often includes severe food allergies.
  • STAT3 mutations more commonly involve pulmonary structural abnormalities, retained primary teeth, fractures from minor trauma, and less severe atopic dermatitis or food allergies. Unique features include neonatal pyoderma and characteristic facial features.
• Tyrosine kinase 2 (TYK2) deficiency: TYK2 is a member of the JAK kinase family. Both STAT3 and TYK2 defects impair Th17 function, leading to HIES-like symptoms. However, TYK2 deficiency is rarer and differs clinically, often presenting with atopic dermatitis and viral skin infections.
• Phosphoglucomutase 3 (PGM3) deficiency: Features include elevated IgE, eczema, recurrent respiratory infections, pneumonia, candidiasis, and abscesses. It also causes bone marrow failure and neutropenia but lacks characteristic facial features.
• Zinc finger protein 341 (ZNF341) abnormality: ZNF341 encodes a transcriptional regulator of STAT3 expression. This newly discovered genetic cause of HIES is not yet well characterized.
• Wiskott-Aldrich syndrome (WAS): WAS patients exhibit thrombocytopenia, small platelets, and possible bruising. Abscesses are uncommon, and characteristic facial features are absent.
• Severe combined immunodeficiency (SCID): A group of disorders with susceptibility to infections and possible IgE elevation. Flow cytometry typically shows markedly reduced T-cell counts.

TREATMENT

Which department should patients with Hyper IgE Syndrome visit?

This disease usually begins in infancy and generally requires a visit to the pediatrics department. Some cases may also be referred to rheumatology and immunology.

How is Hyper IgE Syndrome treated?

Currently, there are no high-quality prospective randomized controlled trials to support treatment measures. Most recommendations are based on observational data and clinical experience.

The primary treatment goals are to control itching and eczema-like dermatitis, prevent infections, and avoid severe systemic infections.

• Skin conditions: Treatment for eczema-like dermatitis is similar to that for atopic dermatitis. However, systemic steroids and cyclosporine should be avoided. Topical calcineurin inhibitors and phototherapy may be used.
• Prophylactic antibiotics: Prophylactic use of trimethoprim-sulfamethoxazole is effective in preventing staphylococcal skin infections (including abscesses), sinusitis, otitis media, and possibly pneumonia. This approach is similar to that for chronic granulomatous disease. Antifungal prophylaxis may follow guidelines for HIV patients.
• Infection treatment: Deep bacterial infections require aggressive systemic antibiotic therapy and may need surgical drainage. Clinicians should remain vigilant for osteomyelitis. Oral and topical antifungals are effective for chronic mucocutaneous candidiasis.
• Managing pulmonary complications: Large, persistent pneumatoceles may require segmental or even lobar resection, though this is rare. Prophylactic antibiotics may reduce lung complications.
• Immunomodulatory therapy: Recombinant interferon-γ may be beneficial, but high-quality prospective randomized trials are lacking. Intravenous immunoglobulin benefits are uncertain unless immunoglobulin/IgG subclass levels are low with impaired antibody responses.
• Bone-targeted therapy: Bisphosphonates may improve bone density, but their effect on fracture risk is unclear. Calcium and vitamin D supplementation are similarly uncertain.
• Bone marrow transplantation: May improve long-term outcomes, but higher-quality clinical trials are needed for confirmation.

What is the prognosis for Hyper IgE Syndrome patients?

The prognosis is generally poor, with some patients dying from severe pulmonary infections. Additionally, lymphoma may develop, which further worsens the prognosis.

DIET & LIFESTYLE

What should patients with hyper IgE syndrome pay attention to in daily life?

Reducing infection risk is crucial. Therefore, avoid areas with high risk of infectious diseases, wash hands frequently, and ensure clean food and drinking water.

As for whether patients can benefit from vaccination? This remains unclear. However, it is generally recommended to avoid live attenuated vaccines.

PREVENTION

Can Hyper IgE Syndrome be Prevented?

Hyper IgE syndrome is a genetic disorder caused by gene mutations and currently cannot be prevented. It is recommended that patients seek genetic counseling before having children to avoid the birth of affected offspring.