FOXN1 plays a crucial role in the development of thymic epithelial cells. Homozygous FOXN1 deficiency leads to T−B+NK+ severe combined immunodeficiency (SCID), whereas FOXN1 haploinsufficiency is linked to T cell lymphopenia and nail abnormalities [1]. There has been an increase in the number of FOXN1 variants identified with the emergence of newborn screening for severe T cell deficiency using T cell receptor excision circle assay. Variants can range from benign to pathogenic [2], with most classified as variants of uncertain significance, making the effects of single-allelic or compound heterozygous mutations less clearly understood [3].
We describe two patients who presented with lymphopenia identified through newborn screening to show the broad phenotype of FOXN1 variants. FM is the first child to non-consanguineous Caucasian parents. Following a positive NBS (newborn screen), second-tier testing identified a mild CD4 T cell lymphopenia (CD4+ 362 × 106/L, 63% naives). At 12 months, persistent moist cough with possible aspiration, recurrent otitis media, sparse hair, and persisting CD4 T cell lymphopenia prompted genetic testing. BM is the third child to non-consanguineous Caucasian parents, with a paternal history of T cell lymphopenia. She was identified on NBS, and second-tier testing identified T cell lymphopenia (CD4+ 63 × 106/L; CD8+ 7 × 106/L). She has remained clinically well with a recent increase in her naive T cells. A targeted panel for inborn errors of immunity revealed heterozygous FOXN1 variants in both patients. Patient FM is heterozygous for FOXN1 c.1465dup,p.(Gln489Profs*40), which is described as likely pathogenic. Patient BM is heterozygous for FOXN1 c.1315del, p.(Leu439Cysfs*111), which has been described as pathogenic.
Despite both these variants being described as pathogenic, these children have had different clinical courses, highlighting the diverse spectrum of the FOXN1 haploinsufficiency phenotype. Furthermore, given the varied phenotype, this leads to discussions surrounding counselling, appropriate antimicrobial prophylaxis, breastfeeding recommendations, and follow-up protocols for these patients.
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