Job syndrome

**Mnemonic: FATED** - **F**acies (coarse features, broad nasal bridge, prominent forehead) - **A**bscesses (cold, noninflammatory staphylococcal abscesses) - **T**eeth (retained primary teeth, delayed shedding) - **E**levated IgE - **D**ermatologic (eczema)

**Genetics and pathophysiology** - Classic form: autosomal dominant, loss-of-function (dominant-negative) mutation in STAT3. - STAT3 is needed for Th17 differentiation, which signals through IL-6, IL-21, and IL-23. - Th17 cells make IL-17 and IL-22. These recruit and activate neutrophils and promote antimicrobial peptide (β-defensin) production at skin and mucosal surfaces. - Without Th17 cells, neutrophil recruitment is poor. This causes "cold" abscesses, which lack warmth, erythema, and other typical inflammatory signs, and it also causes mucocutaneous candidiasis. - The cause of the high IgE is not fully understood. It is thought to reflect immune dysregulation, with a Th2-skewed environment and increased IL-4 effect. - Less common: autosomal recessive forms (DOCK8, TYK2, and others). DOCK8 deficiency gives more viral skin infections (HSV, molluscum, warts), severe allergies, and a risk of malignancy.

**Clinical features** - Recurrent cold staphylococcal skin abscesses (S. aureus), usually starting in infancy - Recurrent sinopulmonary infections (S. aureus, S. pneumoniae, H. influenzae). Pneumatoceles can form and become secondarily infected with Aspergillus. - Chronic mucocutaneous candidiasis - Eczematoid dermatitis - Coarse facies - Retained primary teeth because of failed resorption of the roots - Skeletal and connective tissue abnormalities: minimal-trauma fractures, scoliosis, hyperextensible joints, craniosynostosis - Delayed shedding of the umbilical cord is not a feature. That points to LAD-1 and is a key distinction. - Vascular abnormalities such as coronary artery aneurysms can occur.

**Labs and diagnosis** - Markedly elevated serum IgE, usually >2000 IU/mL - Eosinophilia - Normal or low IFN-γ and low IL-17 on cytokine testing - Normal neutrophil oxidative burst, so a negative nitroblue tetrazolium or DHR test helps distinguish it from CGD - Diagnosis is supported by genetic testing for STAT3 and by a clinical scoring system (NIH score).

**Differential (high-yield comparisons)** - **CGD** (NADPH oxidase defect): catalase-positive organisms, abnormal DHR/NBT, granulomas - **LAD-1** (CD18 integrin defect): delayed umbilical cord separation, neutrophilia, no pus formation - **Chediak-Higashi** (LYST defect): partial albinism, giant lysosomal granules, neuropathy - **Wiskott-Aldrich**: eczema, thrombocytopenia, recurrent infections, with low or normal IgM and high IgE and IgA - **Chronic mucocutaneous candidiasis** (e.g., AIRE or IL-17 pathway defects): recurrent Candida infections of skin and mucosa

**Management** - Lifelong prophylaxis against staphylococcal infection (TMP-SMX) - Antifungal prophylaxis as needed - Aggressive treatment of infections, with drainage of abscesses when needed - Skin care for the eczema - Surgical management of pneumatoceles and bronchiectasis when needed - Hematopoietic stem cell transplantation is used mainly for DOCK8 deficiency and has a limited role in STAT3 disease.

**Name origin:** Named after the biblical Job, who was afflicted with boils. Early descriptions were of red-haired girls with recurrent "cold" boils, which is why it was called Job syndrome. The term "Hyper-IgE syndrome" is now preferred.