Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease.

Clinical analysis of our cohort leads us to define NBO as a distinct disease entity with three clinical presentations: acute NBO, chronic recurrent multifocal osteomyelitis or persistent chronic NBO. Diagnostic criteria were proposed to differentiate NBO from diseases with similar clinical presentation.

Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

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.

Objective To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/ EUROTRAPS international registry. Methods A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. Results Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. Conclusions In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.

This is the largest reported case series of CNO patients, showing that the range of associated clinical manifestations is rather heterogeneous. The study confirms that the disease usually presents with an early teenage onset, but it may also occur in adults, even in the absence of mucocutaneous manifestations.

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Objective. To accurately differentiate nonbacterial osteitis (NBO) from other bone lesions by applying a clinical score through the use of validated diagnostic criteria.Methods. A retrospective study was conducted to assess data on patients from a pediatric clinic and an orthopedic tertiary care clinic, using administrative International Classification of Diseases codes as well as laboratory and department records from 1996 to 2006. Two hundred twenty-four patients older than age 3 years who had either NBO (n ‫؍‬ 102), proven bacterial osteomyelitis (n ‫؍‬ 22), malignant bone tumors (n ‫؍‬ 48), or benign bone tumors (n ‫؍‬ 52) were identified by chart review. Univariate logistic regression was used to determine associations of single risk factors with a diagnosis of NBO, and multivariable logistic regression was used to assess simultaneous risk factor associations with NBO. Conclusion. The proposed scoring system helps to facilitate the diagnostic process in patients with suspected NBO. Use of this system might spare unnecessary invasive diagnostic and therapeutic procedures. Results. NBO was best predicted by a normal blood cell count (odds ratio