Hyper IgE Syndrome

Background

• Hyper IgE syndrome (HIES) is a group of rare primary immunodeficiency disorders characterized by recurrent sinopulmonary and skin infections, chronic eczema, eosinophilia, and elevated serum IgE.
• Type 1 HIES refers to autosomal dominant disorder caused by pathogenic variants in STAT3, and is the most common type.
• Type 2 HIES refers to autosomal recessive disorder caused by pathogenic variants in DOCK8, PGM3, TYK2, or as-of-yet undefined genetic variants.
• DOCK8-mediated HIES is associated with greater mortality than other HIES types due to higher prevalence of invasive infections.

Evaluation

• Patients with HIES typically present with recurrent sinopulmonary and skin infections, chronic eczema, high serum IgE, and eosinophilia.
• Characteristic features of autosomal dominant (STAT3-mediated) HIES include newborn rash, specific craniofacial abnormalities, scoliosis, retained primary teeth, and parenchymal brain lesions.
• Autosomal recessive HIES is characterized by eczema, asthma, and often multiple IgE-mediated allergies to foods and environmental allergens.
  • DOCK8-mediated HIES may be characterized by autoimmune vasculopathy and malignancy including HPV-associated squamous cell carcinoma or EBV-associated Burkitt lymphoma and diffuse large B-cell lymphoma
  • PGM3-mediated HIES may be characterized by neurocognitive defects including intellectual disability and psychomotor impairment.
• The immunologic phenotype varies for different HIES types.
  • Patients with autosomal dominant HIES may have markedly elevated IgE levels (> 20,000 units/mL in some patients), reduced CD4 T helper 17 (Th17) responses, and reduced memory B cells.
  • Patients with DOCK8-mediated HIES may have borderline high or high IgE levels, reduced specific antibody production, reduced naive T cells, normal or reduced Th17 cells, and progressive lymphopenia.
  • Patients with PGM3-mediated HIES may have cytopenias (notably neutropenia and CD8 lymphopenia) and elevated serum IgA, IgM, and IgG.
• Definitive diagnosis may be established with identification of pathogenic variant by genetic testing.
• Consider National Institutes of Health (NIH) HIES score to identify patients for specific genetic testing.

Management

• Therapy is aimed at treatment and prevention of complications (Weak recommendation), including:
  • therapeutic and prophylactic antimicrobial therapy
  • management of allergic manifestations
  • prevention of fractures
  • extraction of retained primary teeth
  • management of malignancy
  • treatment of vasculopathy
• Patients with STAT3-mediated HIES may benefit from immunoglobulin (Ig) replacement or interferon-gamma therapy (Weak recommendation).
• Patients with DOCK8-mediated HIES and poor antibody production may benefit from Ig replacement therapy (Weak recommendation).
• Hematopoietic stem cell transplantation (HSCT) may be considered, particularly for patients with DOCK8-mediated HIES due to high rates of morbidity and mortality (Weak recommendation).
• Surgery may be considered for select patients such as those with retained primary teeth, severe scoliosis, or pulmonary complications not responsive to medical therapy.