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 <i>FOXN1</i> (forkhead box N1) gene. This case suggests that previously healthy carriers of heterozygous <i>FOXN1</i> 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 <i>FOXN1</i> mutations are required to clarify their clinical significance and inform evidence-based management approaches.