Background Hyper-IgE Syndrome (HIES) is a rare, autosomal dominant (AD) immunodeficiency characterized by eczema, Staphylococcus aureus skin abscesses, pneumonia with pneumatocele formation, Candida infections, and skeletal/connective tissue abnormalities. Recently it was shown that heterozygous STAT3 mutations cause AD-HIES. Objective To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of HIES patients. Methods We sequenced the STAT3 gene in 38 HIES patients (NIH-score >40 points) from 35 families, quantified TH17 cells in peripheral blood, and evaluated tyrosine phosphorylation of STAT3. Results Most STAT3 mutations in our cohort were in the DNA-binding domain (DBD) (22/35 families) or SH2 domain (10/35), and were missense mutations. We identified two intronic mutations resulting in exon skipping and in-frame deletions within the DBD. In addition, we identified two mutations located in the transactivation domain downstream of the SH2 domain: A ten amino acid deletion and an amino acid substitution. In one patient, we were unable to identify a STAT3 mutation. TH17 cells were absent or low in the peripheral blood of all patients who were evaluated (n=17). IL-6 induced STAT3-phosphorylation was consistently reduced in patients with SH2 domain mutations, but comparable to normal controls in patients with mutations in the DBD. Conclusion Heterozygous STAT3 mutations were identified in 34/35 unrelated HIES families. Patients had impaired TH17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation. Clinical implication Mutations in STAT3 and decreased TH17 cells identify individuals with AD-HIES, thereby allowing timely diagnosis and early treatment of these patients. Capsule summary Results from this patient cohort expand the spectrum of heterozygous STAT3 mutations in AD-HIES, and demonstrate impaired development of TH17 cells in all and reduced STAT3-phosphorylation in patients with SH2-domain mutations.

Background Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Comèl-Netherton syndrome, an autosomal-recessive disease characterized by congenital ichthyosis, bamboo hair, and atopic diathesis. Despite increased frequency of infections, the immunocompetence of Comèl-Netherton syndrome patients has not been extensively investigated. Objective To define Comèl-Netherton syndrome as a primary immunodeficiency and to explore the benefit of IVIG replacement therapy. Methods We enrolled nine patients with Comèl-Netherton syndrome, sequenced SPINK5, and analyzed LEKTI expression by immunohistochemistry. Immune function was assessed by measuring cognate immunity, serum cytokine-levels and natural killer cell cytotoxicity. Results All patients presented with recurrent skin infections caused predominantly by Staphylococcus aureus. All but one reported recurrent respiratory tract infections; 78% had sepsis and/or pneumonia; 67% suffered from recurrent gastroenteritis and failure to thrive. Mutations in SPINK5 – including six novel mutations- were identified in eight patients. LEKTI expression was decreased or absent in all patients. Immunologic evaluation revealed reduced memory B cells and defective responses to vaccination with Pneumovax® and bacteriophage phiX174, characterized by impaired antibody amplification and class-switching. Immune dysregulation was suggested by a skewed TH1-phenotype and elevated proinflammatory cytokine levels, while serum concentrations of the chemokine RANTES and NK cell cytotoxicity were decreased. Treatment with intravenous immunoglobulin substitution resulted in remarkable clinical improvement and temporarily increased NK cell cytotoxicity. Conclusion These data provide new insights into the immunopathology of Comèl-Netherton syndrome and demonstrate that this multisystem disorder, characterized by lack of LEKTI expression in epithelial cells, is complicated by cognate and innate immunodeficiency that responds favorably to IVIG therapy.

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