Refractory infantile IPEX with Treg-restricted FOXP3null expression caused by a novel variant in FOXP3

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a life-threatening monogenic inborn error of immunity caused by pathogenic variants in the FOXP3 gene. In this report, we describe the clinical and immunologic consequences of a novel FOXP3 variant in an infant with refractory IPEX syndrome. Rapid whole-genome sequencing revealed a missense variant c.1050C>G (p.Ile350Met) in the forkhead domain of FOXP3. FOXP3 expression was abrogated in the regulatory T cell (Treg) subset but was maintained at low levels in activated effector T cells. The frequency of Treg-specific demethylated region (TSDR)-demethylated T cells was within normal range at birth, but it increased to pathologically high levels at 2 wk of age, prior to manifestation of disease symptoms. These results support the clinical relevance of the TSDR-demethylated cell percentage in evaluation of disease activity in IPEX. This case highlights a severe form of IPEX syndrome refractory to multiple immunosuppressive agents and the importance of early immunological studies to verify the clinical significance of novel genetic findings.