Broadening the Phenotypic Spectrum of Forkhead Box N1 Gene Mutations

A man in his 50s develops signs of immune dysfunction (recurrent chest infections and new-onset chronic diarrhoea), alongside a history of multiple distinct malignancies and nail dystrophy. Immunological testing reveals T-cell lymphopenia and hypogammaglobulinaemia. Whole genome sequencing reveals a heterozygous c.1465del mutation in the FOXN1 (forkhead box N1) gene. This case suggests that previously healthy carriers of heterozygous FOXN1 mutations may be at risk of developing immune dysfunction in later life. Potential reasons for the severe and delayed phenotype include a dominant-negative effect of the resultant protein (p.Gln489ArgfsTer61), age-related involution of the thymus and previous chemoradiotherapy. Further studies on heterozygous FOXN1 mutations are required to clarify their clinical significance and inform evidence-based management approaches.