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.

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The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.

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One dose of varicella vaccine provided high protection against moderate and severe varicella disease for a period of up to 5 years after vaccination. However, further effectiveness data are needed to assess long-term protection.