Known causes of eosinophilia were excluded, and serum levels of I元, IL5, and GM-CSF were similar to controls. Additional features included poor overall growth, short stature, hepatosplenomegaly, eosinophilic infiltration of the liver and gastrointestinal tract, and autoimmune thyroid disease. (2017) reported a mother and her 2 sons, aged 2 and 6 years, with a hyperinflammatory disorder manifest as severe corticosteroid-resistant pruritic atopic dermatitis, environmental allergies, and asthma associated with eosinophilia, but normal IgE levels. This pharmacologic rescue of JAK hyperactivity was confirmed in in vitro studies of patient cells, which showed a decrease in STAT phosphorylation after treatment.ĭel Bel et al.

Treatment with tofacitinib, a pan-JAK inhibitor, resulted in nearly complete resolution of clinical symptoms and laboratory abnormalities. The mutant JAK1 protein was itself hyperphosphorylated compared to controls in addition, there was hyperphosphorylation of other signaling partners, including JAK2 ( 147796), TYK2 ( 176941), and JAK3 ( 600173), and activation of several noncanonical STAT signaling pathways. In vitro functional studies in patient-derived B cells and transduced cells showed that the mutation caused increased basal phosphorylation of STAT proteins and active target gene transcription in the absence of cytokine stimulation, as well as hyperresponsiveness to cytokine stimulation compared to controls, consistent with a gain-of-function effect. PCR analysis of patient tissues showed that it was a somatic mutation that occurred very early in development, estimated at the first 12 cell divisions between fertilization and gastrulation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in any public databases.

(2020) identified a de novo heterozygous missense mutation in the JAK1 gene (S703I 147795.0002). In an 18-year-old woman with AIIDE, Gruber et al. Treatment with ruxolitinib, a JAK1/2 inhibitor, significantly reduced this hyperresponsivity and resulted in clinical improvement. In vitro studies of patient B and T cells showed enhanced STAT1 ( 600555)/STAT3 ( 102582) phosphorylation and activation in response to stimulation, consistent with a gain-of-function effect. The mutation, which was found by a combination of whole-exome and targeted Sanger sequencing, segregated with the disorder in the family. (2017) identified a heterozygous missense mutation in the JAK1 gene (A634D 147795.0001). In a mother and her 2 sons with AIIDE, Del Bel et al.

Flo progressive weight gain 2017