hyper-IgE syndrome

**Etiology/Pathophysiology** - Classic (autosomal dominant, "Job syndrome," HIES type 1): dominant-negative loss-of-function mutation in STAT3. STAT3 is needed for signaling downstream of IL-6, IL-21, and IL-23, which drive Th17 differentiation. Result: decreased Th17 cells and decreased IL-17 and IL-22, so neutrophil recruitment is poor. Failure to recruit neutrophils to skin and lung mucosa causes "cold" abscesses (little warmth, erythema, or tenderness) and Staph aureus and Candida infections. - Why IgE is high: the mechanism is not fully understood. It is associated with impaired IL-21/STAT3 regulation of B cells and IgE class switching. - Other forms: AR DOCK8 deficiency (combined immunodeficiency with eczema, severe viral skin infections such as HSV, molluscum, and HPV, plus malignancy risk; treated with HSCT) and AR TYK2 deficiency (mycobacterial and viral infections). PGM3 deficiency is another AR cause.

**Clinical features (mnemonic: FATED)** - Facies: coarse features, broad nasal bridge, prominent forehead - cold (non-inflamed) Abscesses (Staph aureus) - retained primary Teeth (delayed shedding of deciduous teeth) - increased IgE - Dermatologic: eczema - Other: eosinophilia, pneumonia with pneumatoceles (Staph aureus, Haemophilus, Strep pneumoniae) and later Aspergillus colonization, chronic mucocutaneous candidiasis, hyperextensible joints, scoliosis, osteopenia, and pathologic fractures with minimal trauma, craniosynostosis, and coronary artery aneurysms.

**Diagnosis** - Serum IgE >2000 IU/mL (often much higher), eosinophilia, and normal levels of other immunoglobulins (IgG, IgA, and IgM are usually normal). Specific antibody responses may be impaired. - Reduced Th17 cells on flow cytometry. Confirm with STAT3 (or DOCK8) genetic testing. A clinical scoring system (NIH HIES score) is also used. - Neutrophil oxidative burst is normal (NBT/DHR test normal), which distinguishes it from CGD.

**Treatment** - Lifelong prophylaxis with antistaphylococcal antibiotics (TMP-SMX), antifungals as needed, skin care (bleach baths, emollients), prompt drainage of abscesses, and surgical management of pneumatoceles when complicated. - IVIG in selected patients. HSCT for DOCK8 deficiency (and sometimes considered for STAT3).

**High-yield differentials** - Chronic granulomatous disease (NADPH oxidase defect): catalase-positive organisms, abnormal DHR/NBT, granulomas. - Wiskott-Aldrich syndrome: thrombocytopenia with small platelets, eczema, recurrent infections, and increased IgE and IgA with decreased IgM (WAS gene, X-linked). - Leukocyte adhesion deficiency type 1: delayed umbilical cord separation, marked neutrophilia, no pus (CD18 defect). - Chediak-Higashi syndrome: LYST mutation, giant lysosomal granules, partial albinism, and neuropathy. - Atopic dermatitis: elevated IgE, but no deep-seated infections.

**Board pearl:** A child with eczema-like rash, recurrent "cold" staph abscesses, retained baby teeth, fractures, and very high IgE: think STAT3 mutation with decreased Th17 (IL-17) response. Named for Job, who was afflicted with boils in the Bible.