Clinical variance in an international cohort of families with dominant-negative FOXN1 mutations

Abstract

Transcription factor Forkhead box protein N1 (FOXN1) regulates thymic epithelial cell development. Bi-allelic and compound heterozygote loss-of-function mutations result in nude-severe combined immune deficiency with athymia, alopecia, and nail dystrophy requiring thymus transplantation. Dominant-negative heterozygous variants have incomplete and highly variable phenotypes. We present an international cohort of families carrying dominant negative mutations with variable clinical presentation, course, and outcomes.

Methods Patient medical records and diagnosing physicians were consulted.

Results We have access to 11 FOXN1 dominant-negative heterozygotes from 4 families with highly variable intrafamilial clinical courses and management. All variants locate near the C terminus, like variants in Rota et al. [1]. Immunological phenotype included 5/11 with Omenn syndrome (OS) early in life, otherwise presenting as asymptomatic (2/11) or with T cell lymphopenia (4/11), characterized by persistently low naïve T cells, and specific antibody deficiency (1/11) even in middle age. Alopecia and/or nail dystrophy was only noted in 1/11 patients. OS treatments ranged from conservative management (1/5), short-term steroids (1/5), long-term prednisolone alone (1/5), cyclosporine and prednisolone (1/5), and 1/5 OS patients received a bone marrow transplant prior to genetic diagnosis and later expired. (3/11) patients were placed on immunoglobulin replacement therapy. Only 3/11 patients experienced adverse outcomes, with 1/11 deaths. Other adverse outcomes include severe herpesviridae infections: Varicella pneumonia and CMV retinitis, respectively. 2/11 patients experienced EBV viremia and 2/11 with CMV viremia. 1/2 families tested were positive for anti-IFNα autoantibodies. Only one patient is being considered for thymic transplant.

Conclusions This cohort demonstrates intrafamilial variability ranging from asymptomatic symptoms to OS, which has seldom been described in athymia patients. Heterogeneity indicates a need for distinct longitudinal treatment protocols for dominant negative FOXN1 patients, including lifelong protective immunoglobulin replacement therapy, and the possibility of thymic transplant for best outcomes, which has not been performed in FOXN1 heterozygotes before.