FOXN1 – T-Cell Immunodeficiency with Congenital Alopecia and Nail Dystrophy

Forkhead box N1 (FOXN1) is a transcription factor critical for thymic epithelial cell (TEC) differentiation and T-cell development. Autosomal recessive biallelic loss-of-function variants in FOXN1 disrupt TEC formation, leading to congenital alopecia, nail dystrophy and severe T-cell immunodeficiency (nude severe combined immunodeficiency phenotype). Early hematopoietic stem cell transplantation (HSCT) can be life-saving, although thymic transplantation addresses the stromal defect most directly.

Inheritance is autosomal recessive, with a reported homozygous FOXN1 mutation in a Turkish patient presenting neonatal T-cell immunodeficiency, alopecia and nail dystrophy treated by sibling HSCT (PMID:37146104). No additional familial segregation data have been reported for this specific phenotype.

Variant spectrum in FOXN1 includes frameshift loss-of-function and missense alleles. In heterozygous individuals, variants such as c.1205del (p.Pro402LeufsTer148) have been associated with T-cell lymphopenia but variable hair/nail involvement (PMID:39008056).

Foxn1 knockout and mutant mouse models recapitulate human TEC hypoplasia and severe lymphopenia. Foxn1(Δ/Δ) mice exhibit blocks at DN1 and DP thymocyte stages, impaired positive/negative selection, and peripheral T-cell dysfunction consistent with human immunodeficiency (PMID:21079757).

Mechanistic studies reveal that FOXN1 participates in higher-order nuclear condensates essential for transcriptional activity. C-terminal mutations act dominantly to displace wild-type FOXN1 from condensates, impairing TEC differentiation and causing athymia in heterozygotes (PMID:34860543).

Integration of genetic and functional data supports a loss-of-function mechanism underlying the congenital alopecia–T-cell immunodeficiency–nail dystrophy syndrome. While only a single homozygous proband has been documented to date, concordant murine and cellular models provide robust experimental validation.

Key Take-home: Biallelic FOXN1 loss-of-function is a clinically actionable cause of congenital alopecia with severe T-cell immunodeficiency and nail dystrophy; genetic diagnosis directs optimal immunologic and thymic therapies.

References

• Journal of pediatric hematology/oncology • 2023 • Immune Reconstitution Inflammatory Syndrome After Hematopoietic Stem Cell Transplantation in a FOXN1-deficient Patient PMID:37146104
• PloS one • 2010 • Impaired thymic selection and abnormal antigen-specific T cell responses in Foxn1(Δ/Δ) mutant mice PMID:21079757
• Science advances • 2021 • FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency PMID:34860543
• ImmunoHorizons • 2024 • Peripheral T Cell Development and Immunophenotyping of Twins with Heterozygous FOXN1 Mutations PMID:39008056

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