SUMMARY
1. STAT3 Deficiency (Hyper IgE Syndrome) is an autosomal dominant primary immunodeficiency characterized by the following clinical features:
-Severe Eczema
-Recurrent bacterial skin abscesses and pneumonias
-Pneumatoceles
-Coarse facial features - wide nose, deep-set eyes, prominent chin and forehead
-Delayed shedding of primary teeth
-Pathologic fractures
-Scoliosis
-Joint hypermobility
-Coronary artery dilation and aneurysms
-Increased risk for lymphoma
2. A scoring system developed by the National Institutes of Health (NIH) is a useful tool for quantifying the clinical and laboratory features of suspected patients. Using this scoring system, most autosomal dominant HIES patients have a score above 40.
3. Staphylococcus aureus is the most common infectious organism encountered by patients. Streptococcus pneumoniae and Haemophilus influenzae can cause pulmonary disease. Pneumatoceles can become superinfected by Pseudomonas and Aspergillus. Patients can develop chronic mucocutaneous candidiasis involving the oral mucosa and nails. Rare cases of Pneumocistis jirovecii infection have been reported.
4. Laboratory findings include elevated IgE and eosinophilia. Elevated IgE does not correlate with severity of disease. Total immunoglobulin levels are normal or elevated but patients may have poor response to protein and polysaccharide immunizations. Neutrophil killing is intact but neutrophil chemotaxis is impaired. Th17 cells are markedly reduced. STAT3 phosphorylation in response to IL-6 stimulation is also reduced.
5. This diagnosis should be suspected in patients with classic infections, physical findings, and elevated IgE levels. Elevated IgE is a non-specific finding and can be elevated in patients with other atopic disease such as asthma or eczema. The presence of invasive infections helps to distinguish HIES from benign atopic dermatitis with elevated IgE.
6. STAT3 gene sequencing confirms the diagnosis
7. Antibiotic prophylaxis with trimethoprim-sulfamethoxazole (2.5mg/kg of TMP component) is useful for preventing staphylococcal infections. Effective care of dermatitis can help to maintain the skin barrier and prevent infections. Patients with chronic mucocutaneous candidiasis may benefit from antifungal prophylaxis (ex. Itraconazole 5mg/kg once daily). Patients with specific antibody deficiency benefit from IVIG replacement therapy.
OVERVIEW
STAT3 Deficiency (Hyper IgE Syndrome) is an autosomal dominant primary immunodeficiency characterized by recurrent staphylococcal skin abscesses, pneumonia with pneumatocele formation, eczematous dermatitis, and elevated serum IgE levels (usually over 2,000 IU/ml).
Staphylococcus aureus is the most common infectious organism encountered by patients. Streptococcus pneumoniae and Haemophilus influenzae can cause pulmonary disease. Pneumatoceles can become superinfected by Pseudomonas and Aspergillus. Patients can develop chronic mucocutaneous candidiasis involving the oral mucosa and nails. Rare cases of Pneumocistis jirovecii infection have been reported.
In addition to infections, patients have a unique set of somatic findings including characteristic facial features (broad nasal base/nasal bridge, frontal bossing, deep set eyes, and prominent chin), delayed shedding of primary teeth, pathologic fractures with minimal trauma, scoliosis, and joint hypermobility. Vascular anomalies have been described in patients including coronary and extracoronary arterial tortuosity, dilation, and aneurysms. Patients appear to have an increased risk of Hodgkin’s and non-Hodgkin’s lymphoma.
PATHOGENESIS
STAT3 (signal transducer and activator of transcription 3) is involved in mediating cytokine signaling via the JAK-STAT pathway. As a result, patients have defective differentiation of IL-17 secreting T cells (Th17 cells). IL-17 stimulates granulopoiesis through induction of G-CSF, recruit neutrophils to the site of infection through induction of IL-8 and stimulate production of antimicrobial peptides such as β-defensins.
EVALUATION
The diagnosis of HIES should be considered in patients with severe dermatitis starting during infancy, recurrent skin abscesses and pneumonia, and characteristic musculoskeletal abnormalities.
STEP 1: NIH Hyper IgE Scoring System (available in the resource section)
The use of this scoring system to quantify the above laboratory results and clinical findings is useful.
HIES is a multi-system disease with many features, one of which is high IgE - elevated IgE alone without significant infections or other somatic findings will yield a very low predictive score.
-Classic AD-HIES patients often have scores above 40.
-AR-HIES patients will have a significantly lower score given the absence of pathologic fractures, scoliosis, hyperextensible joints, and pneumatocele formation.
STEP 2: Initial screening laboratory studies.
-CBC with Differential
-Serum IgE levels
-IgG, IgM, IgA
-Specific antibody responses to vaccines
-Lymphocyte subset enumeration by flow cytometry
-Lymphocyte Mitogen proliferation
-Th17 Subset enumeration by flow cytometry
-pSTAT3 flow cytometry (following IL-6 stimulation)
-Eosinophil counts are frequently elevated in HIES. Eosinophilia is more severe in AR-HIES.
-Serum IgE is often above 2,000 IU/ml and can be as high has 50,000 IU/ml. However, some patients have been reported to have IgE levels below 1,000 IU/ml.
-Impaired specific antibody responses have been described in HIES.
-Decreased T-cell, B-cell, and NK-cell numbers have been described in AR HIES (DOCK8) patients. These values are normal in STAT3 deficiency.
-Th17 cells are markedly reduced (testing available at Seattle Childrens and MCW)
-STAT3 phosphorylation following IL-6 stimulation is reduced (testing available at Seattle Childrens)
STEP 3: NIH Hyper IgE Scoring System (available in the resource section)
The use of this scoring system to quantify the above laboratory results and clinical findings is useful.
HIES is a multi-system disease with many features, one of which is high IgE - elevated IgE alone without significant infections or other somatic findings will yield a very low predictive score.
-Classic AD-HIES patients often have scores above 40.
STEP 4: Mutational Analysis
STAT3 gene sequencing confirms the diagnosis and is commercially available
MANAGEMENT
1. Skin Care – Eczema should be treated with emollients and topical anti-inflammatory medications. Superinfection of eczema requires treatment with systemic antibiotics. Bleach baths 3 times weekly can be helpful to decrease cutaneous Staphylococcus colonization.
2. Prophylactic Antibiotics - Daily trimethoprim-sulfamethoxazole (2.5mg/kg of TMP component twice daily) is useful to decrease skin and lung infections.
3. Prophylactic Antifungals – Daily antifungal prophylaxis with an –azole (fluconazole, itraconazole) may be useful for patients suffering from chronic mucocutaneous candidiasis (ex. Itraconazole 5mg/kg once daily).
4. Intravenous Immune Globulin (IVIG) therapy – While patients do not typically have low serum IgG, some patients do have poor specific antibody responses and thus may benefit from IVIG replacement therapy. Typical dosing is 400-600mg per kg administered once a month by IV or once a week by subcutaneous infusion.
5. Interferon Gamma – There have been mixed results with use of interferon gamma in STAT3 deficiency patients. Currently there is not enough evidence to utilize this therapy on a routine basis for this disease.
RESOURCES
Diagnostic Resources
1. NIH Hyper IgE Scoring System
2. Th17 subset enumeration and pSTAT3 by flow cytometry - Seattle Childrens
3. STAT3 Gene Sequencing - Seattle Childrens
Literature Resources
1. Yong 2012
Update on Hyper IgE Syndrome review
2. Holland 2007
STAT3 mutations in Hyper IgE (NEJM)
3. Schimke 2010
Immunologic and clinical findings to differentiate Hyper IgE syndromes from atopic dermatitis
4. Angelini 2001
JC virus PML in a Hyper IgE patient
5. Freeman 2006
Pneumocystis infection in Hyper IgE
6. Freeman 2007
Fatal Pseudomonas and Aspergillus infections in Hyper IgE