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case_images: Photographs of the CMC manifestations in the two boys: Candida paronychias and onychodystrophic thumbnails (A, B) and periocular seborrheic eczema (C) in the index patient 1, and oral candidiasis in his brother (D).
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case_images: A 4-year-old boy (patient 1) presented with CMC-associated recurring oral candidiasis and candida-associated paronychia since infancy, body-wide scaly seborrheic eczemas that extended to the eyelids, and a dystrophic growth of both thumbnails due to a chronic inflammation of the nail folds ( Figure 1 ). His 14-month-old brother (patient 2) developed a severe oral thrush 3 months later ( Figure 1D ).
case_images: Result of the pathogenic variant screening in our CMC family. In the index patient, targeted pathogenic variant screening revealed a heterozygous c.1013G>T (p.Gly338Val) missense pathogenic variant in the STAT1 gene, which was subsequently also identified in the peripheral blood of his brother and in the fibroblasts of his father with Sanger sequencing the respective PCR-amplified Exon 11, but not in the healthy mother.
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case_images: TruSight  One Panel to sequence DNA that was extracted from the older boy's peripheral blood cells and focused our screening efforts on the three most likely responsible genes, namely, STAT1, IL17RA, and AIRE. This approach uncovered a hitherto undescribed heterozygous STAT1 missense variant c.1013G>T (p.Gly338Val) that affects the DNA-binding domain ( Figure 2 ).
case_images: Results of the analyses of the functional consequences of the STAT1 c.1013G>T (p.Gly338Val) missense pathogenic variant. Compared to healthy controls, stimulation with interferon-alpha as well as interferon-gamma leads to the hyperphosphorylation of STAT1 in the monocytes (left) of the index patient and his brother (not shown). Conversely, stimulation with the NF-kappaB activator phorbol myristate acetate and ionomycin revealed the impaired expression of interleukin-17 as well as interferon-gamma in their CD45RO+CD4+ T cells. Together, these findings provide persuasive evidence for the GOF effect of this pathogenic variant.
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case_images: To further verify the functional relevance of this novel STAT1 missense variant, we stimulated peripheral blood mononuclear cells (PB-MNCs) of the two brothers with interferon (IFN)-alpha and IFN-gamma, which led to a significant increase in the phosphorylation of STAT1 ( Figure 3 ). T cells ( Figure 3 ). Together, these results clearly proved the GOF nature of this c.1013G>T STAT1 missense variant.