What is Hyper-IgE Syndrome (Job Syndrome)?
Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare primary immunodeficiency disorder characterized by markedly elevated serum IgE levels (often >2000 IU/mL), recurrent staphylococcal skin abscesses and pneumonias with pneumatocele formation, chronic eczema, and distinctive skeletal/connective tissue abnormalities. 1
Two Main Genetic Forms
HIES exists in two distinct genetic forms with overlapping but distinguishable features:
Type 1: Autosomal Dominant HIES (STAT3 mutations)
Most common form caused by heterozygous STAT3 gene mutations 1
Infectious manifestations:
- Recurrent "cold" staphylococcal abscesses (minimal inflammation/warmth)
- Pneumonias with pneumatocele formation leading to bronchiectasis
- Candida infections (mucocutaneous)
- Nontuberculous mycobacterial infections
- Opportunistic viral infections 1
Non-immunologic features (key distinguishing characteristics):
- Characteristic coarse/asymmetric facial features (becomes more prominent with age)
- Hyperextensible joints and bone fragility with fractures from minor trauma
- Scoliosis and osteopenia
- Delayed shedding of primary teeth due to failed root resorption
- Craniosynostosis
- Neonatal dermatitis and chronic eczema
- Midline anomalies
- Increased risk of lymphoma 1
Type 2: Autosomal Recessive HIES (DOCK8 mutations)
- Less common form with DOCK8 gene mutations 1
- Key differences from Type 1:
- NO skeletal or dental abnormalities
- NO pneumatoceles
- More severe allergic manifestations with marked eosinophilia
- Extensive disseminated cutaneous viral infections (molluscum contagiosum, HSV, HPV)
- Autoimmune vasculopathy with CNS involvement
- Higher lymphoma risk
- Variable cellular and humoral immune defects 1
Pathophysiology
Both forms share a common immunologic defect: impaired development and function of IL-17-producing TH17 cells 1. This explains the susceptibility to Candida species and extracellular bacterial infections, as IL-17 is critical for host defense against these pathogens.
Laboratory Findings
- Markedly elevated serum IgE (typically >2000 IU/mL, often >3000 IU/mL) 1, 2
- Eosinophilia (particularly in Type 2)
- Allergen-specific IgE usually absent despite high total IgE 1
- Other humoral and cellular immunity screening typically normal in Type 1
- Low TREC numbers may be present in DOCK8 deficiency 1
Diagnostic Approach
A clinical scoring system based on clinical and laboratory features aids diagnosis of autosomal dominant HIES 1. Key red flags include:
- Recurrent pneumonias with pneumatocele formation
- Cold staphylococcal abscesses
- Characteristic facial features with skeletal abnormalities
- Retained primary teeth
- IgE >2000 IU/mL
Genetic testing with STAT3 or DOCK8 gene sequencing confirms the diagnosis 3, 2.
Clinical Pitfalls
- Variable expressivity: Family members with the same STAT3 mutation can have markedly different disease severity 1
- Somatic mosaicism can produce intermediate/variant phenotypes 1
- Facial features may be subtle or absent in youth, becoming more prominent with age 1
- A rare TYK2 mutation variant exists with skin infections, lung abscesses, and elevated IgE but may present differently with BCG infections and salmonellosis 1