Hyper-IgE Syndrome

Hyper-IgE syndrome is a group of primary immunodeficiencies characterised by markedly raised serum IgE, eczema, recurrent skin and lung infections with Staphylococcus aureus, and eosinophilia. The most common form is autosomal dominant, due to dominant negative STAT3 variants, and also known as Job syndrome.

It is rare, with an estimated incidence of about 1 in 1 million. Autosomal recessive forms include DOCK8 deficiency and PGM3, SPINK5 (Netherton) and other variants. The dominant form affects connective tissue, bone, teeth and vasculature, while DOCK8 deficiency affects viral and cutaneous infection and malignancy risk.

Pathophysiology.

STAT3 variants impair signalling of interleukin-6, interleukin-10, interleukin-21 and interleukin-23, which reduces Th17 cell differentiation. Reduced interleukin-17 and interferon production impairs mucosal defence against Staphylococcus aureus and Candida.

The mechanism of raised IgE is not fully understood. Connective tissue abnormalities arise from impaired STAT3 signalling in non-immune cells.

• Newborn eczema like rash progressing to chronic eczema, with "cold" staphylococcal skin abscesses lacking warmth and erythema.
• Recurrent pneumonia that heals with pneumatocoeles and bronchiectasis, with superinfection by Aspergillus and Pseudomonas.
• Chronic mucocutaneous candidiasis, onychomycosis and sinusitis.
• Non-immune features in the autosomal dominant form: coarse facial features, retained primary teeth, scoliosis, hyperextensible joints, minimal trauma fractures, craniosynostosis, and coronary artery aneurysms.
• DOCK8 deficiency: severe viral skin infections (molluscum, warts, herpes), food allergy, asthma, and squamous cell carcinoma and lymphoma.

Red flags.

• Pneumonia with pneumatocoeles, or fungal lung infection.
• Recurrent staphylococcal abscesses with raised IgE and eosinophilia.
• Malignancy, severe viral skin disease, or neurological features.

• Serum IgE usually over 2000 units/mL, though the level may fluctuate or fall with age. Eosinophilia is common.
• Immunoglobulins (IgG, IgA, IgM), vaccine antibody responses, lymphocyte subsets with Th17 cells, and neutrophil function tests to exclude other defects.
• Genetic testing for STAT3, DOCK8 and other genes. Dental, skeletal, and chest imaging (CT).
• Skin and sputum cultures, and fungal cultures. Aspergillus galactomannan with respiratory infection.

Differential diagnosis. Atopic dermatitis with very high IgE, Wiskott-Aldrich syndrome, Netherton syndrome, chronic granulomatous disease, leucocyte adhesion deficiency, severe combined immunodeficiency (Omenn syndrome), CARD11 deficiency and PGM3 deficiency.

• Long term prophylaxis for Staphylococcus aureus: co-trimoxazole 5 mg/kg/day of the trimethoprim component once daily or in 2 divided doses. Prophylaxis for fungal infection with fluconazole 3 to 6 mg/kg once daily or itraconazole 5 mg/kg once daily.
• Skin care: emollients, dilute bleach baths, topical antiseptics and corticosteroids for eczema. Drain abscesses and treat with antibiotics directed to Staphylococcus aureus.
• Lung: early treatment of pneumonia, airway clearance, treatment of pneumatocoeles and bronchiectasis. Antifungal therapy for aspergillosis (voriconazole). Surgery for lung complications is hazardous because of poor healing.
• Immunoglobulin replacement if specific antibody production is impaired.
• Dental care for retained teeth, bone health with vitamin D and calcium, and cardiovascular surveillance (coronary imaging).
• Haematopoietic stem cell transplantation is the treatment of choice for DOCK8 deficiency and considered for severe STAT3 disease.

Monitoring. Infections, lung imaging and function, bone density, dental review, cardiac imaging, and for DOCK8 deficiency, screening for malignancy.

Referral and escalation. Refer to a paediatric immunology service at diagnosis and early for transplant assessment in DOCK8 deficiency.