Heterozygous FOXN1 variant in an Infant with severe T cell lymphopenia and thymic hypoplasia with improvement of CD4CD45RA within first year of life

FOXN1 encodes a transcription factor that regulates the development of epithelial cells in the thymus and skin. Biallelic pathogenic variants in FOXN1 result in T-B+NK+ SCID due to athymia. In this case, a heterozygous variant presents a milder phenotype. Whole Exome Sequencing by SouthSeq research study We report a non-dysmorphic 4-month-old male hospitalized for PJP and CMV viremia. TREC was undetectable with CD3 1120, CD4 240, CD4CD45RA 70, CD4CD45RO 170, CD8 560, and normal B and NK cells. There was no evidence of maternal engraftment and no thymus noted on imaging. Whole exome sequencing revealed a heterozygous variant in FOXN1 c.961C>T(p.His321Tyr). This mutation was found in his healthy father. Chromosome testing identified mosaicism for monosomy X (20%) and a second cell line with an Isodicentric Y (80%). Upon development of neutropenia, evaluation for a bone marrow failure syndrome included a bone marrow biopsy with normal cellularity and negative laboratory testing for these syndromes. PJP was treated successfully with sulfamethoxazole-trimethoprim and CMV viremia treated with valgancyclovir and CMV immunoglobulin. He was also treated with monthly IVIG, palivizumab, and prophylactic azithromcycin and voriconazole. Patient was discharged when CMV viremia decreased significantly. Four months post-hospitalization, CD4CD45RA doubled to 140. This case details improvement of CD4CD45RA in an infant with heterozygous FOXN1 variant, thymic hypoplasia, PJP pneumonia, and CMV viremia. We would recommend monitoring of CD4CD45RA in these patients given gradual improvement in T cell lymphopenia.