To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.

Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.

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Background and Aims: Data on acute paediatric anaphylaxis presentations to the emergency department (ED) are limited. All allergic presentations to one Australian paediatric ED were studied to determine epidemiological, clinical, and outcome data. Methods: Retrospective, case based study of patients under 16 years attending one metropolitan, paediatric teaching hospital ED in Australia over three years. The medical records of patients presenting with generalised allergic reactions and anaphylaxis satisfying relevant ICD-9-CM diagnostic codes were studied. The incidence, age, sex ratio, co-morbidities, likely aetiology, clinical features, management, and disposal were determined. Results: A total of 526 children with generalised allergic reactions, and 57 with anaphylaxis were included in the study. This represented incidences of 9.3:1000 ED presentations for generalised allergic reactions and 1:1000 for anaphylaxis. There were no fatalities. In anaphylaxis cases, a cause was recognised in 68.4%. Cutaneous features were present in 82.5%. A past history of asthma was reported in 36.8%. Adrenaline was used in 39.3% of severe anaphylaxis cases. The ED alone definitively cared for 97.8% of all patients. Follow up was inadequate in cases of anaphylaxis. Conclusions: This is the first reported incidence figure for paediatric anaphylaxis ED presentations in Australia, and is less than that reported in adults in the same local population. However, the incidence of generalised allergic reactions of 9.3:1000 was greater than in the adults. Virtually all paediatric allergic cases may be managed in the ED alone, provided that the importance of specialist follow up, particularly for severe anaphylaxis, is recognised.

Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.