Transcription factor forkhead box protein N1 (FOXN1) is the master transcription factor required for differentiation and maintenance of thymic epithelial cells (TECs) and is not only required for embryonic thymus development but also for postnatal thymic maintenance. Autosomal recessive FOXN1 deficiency leads to alopecia, nail dystrophy, and nude severe combined immune deficiency (SCID) due to athymia requiring thymus transplantation. Dominant-negative (DN) heterozygous variants, on the other hand, have incomplete and highly variable phenotypes. We hereby present an international cohort of families carrying dominant-negative mutations with variable clinical presentation, course, and outcomes.
Patient medical records and diagnosing physicians were consulted.
We present 15 FOXN1 DN heterozygotes from 7 different families across the world, demonstrating highly variable intrafamilial clinical courses and management. Age at diagnosis ranged from 0.2 to 45 years. Eight patients were male, and seven were female. Four individuals were diagnosed through newborn screening (NBS) for SCID. Immunological phenotype included Omenn syndrome (OS) (6/15), SCID-like disease (1/15), combined immunodeficiency (CID) with autoimmunity complications (1/15), T cell lymphopenia (5/15) or antibody deficiency (2/15), and one asymptomatic individual. Herpesviridae-related complications were prominent, including EBV viremia (3/15), Varicella pneumonia (1/15), severe Varicella infection (1/15), and CMV disease (3/15), one of which presented with CMV retinitis. The severity and management of OS were variable: one patient was managed with monitoring alone, one received immunoglobulin replacement therapy (IgRT) alone, one received antimicrobial therapy only, two received IgRT and antimicrobial prophylaxis, and one was treated with prednisone, cyclosporine, IgRT, and broad antimicrobial prophylaxis. One patient underwent hematopoietic stem cell transplantation (HSCT) before the identification of DN-FOXN1 and died from transplant-related complications. No OS patient required HSCT. Up to date, no patient has received a thymic transplant.
Heterozygous FOXN1 variants have traditionally been considered mild, with immune function often improving over time and without the need for definitive therapies. However, DN-FOXN1 variants appear to carry a broader clinical spectrum, including OS. In our cohort, OS manifestations were variable and could often be managed with supportive care, including IgRT, antimicrobial prophylaxis, and, when indicated, immunosuppression, and none of the patients has required thymic transplantation to date.
