Background and Aims

Hyperactive or constitutive STAT6 signalling is associated to increased Th2 differentiation, responsible of allergic inflammation. STAT6 variants have been associated to food allergies¹ and STAT6 somatic mutations have been identified in 11% of follicular lymphoma.² Recently, STAT6 variants have been detected in two patients with profound allergic immunedysregulation.³

Methods

We describe a clinical case of allergic immunedysregulation. Diagnostic work-up included immunologic investigations using FACS analysis, clinical exome sequencing (CES) and proteomic approach through Olink assay.

Results

A 21yo-girl presented early-onset refractory atopic dermatitis, recurrent respiratory infections, severe asthma, multiple inhalants, drugs and food severe allergies, HPV-negative laryngeal papillary hyperplasia, gastrointestinal disorders with not-specific mucosal infiltrate and chronic EBV infection.

Diagnostic work-up showed hyper-eosinophilia, hyper-IgE (699-12550 kU/L), positive RAST and ISAC test for multiple allergens, normal Ig levels, normal frequency of Tcells and Tregs, reduced frequency of Th17cells, normal circulating Tfhcells, slightly reduced Bcells frequency with normal Bcell maturation, reduced in vitro Tcell proliferation and Bcell antibodies production.

CES disclosed a de novo heterozygous mutation in STAT6 gene (c.1255G>A; p.D419N), predicted pathogenic by ACGM (CADD score 31) not reported in gnomAD, but described in follicular lymphoma. Proteomic analysis showed a baseline higher percent-change in IL-4 level compared to healthy control.

Conclusions

We suggest that the mutation identified in our patient could be responsible of her clinical phenotype and could be stated as a novel Primary Atopic Disorder. More functional studies are ongoing to confirm its pathogenic role and to suggest a targeted therapeutical choice.

¹Allergy. 2018 Jun;73(6):1337-1341.

²Blood. 2015 Jan 22;125(4):668-79.

³medRxiv preprint doi:10.1101/2022.04.25.22274265