In the last decade, diagnostic detection of severe combined immune deficiency (SCID) has improved with the widespread implementation of universal newborn screening (NBS) for SCID in the United States. Our case identifies a novel variant of forkhead box protein N1 (FOXN1) deficiency, identified after NBS.
A 1,683 g male infant, born at 31w2d by spontaneous vaginal delivery in the setting of preterm premature rupture of membranes and maternal chorioamnionitis, was found to have initial NBS inconclusive for SCID. Family history was unremarkable. He was admitted to the neonatal intensive care unit (NICU) for respiratory distress syndrome, prematurity, and hyperbilirubinemia. He developed Enterococcus faecalis urinary tract infection and was treated with piperacillin-tazobactam followed by ampicillin.
Both the second and third NBS remained inconclusive for SCID. Laboratory studies revealed markedly low T lymphocyte counts (cells/uL): CD3+ 208, CD4+ 119, CD8+ 89, CD45RA 67, and CD45RO 25, with normal CD19+ B cells (574) and normal natural killer (NK) cells (158). Eosinophil counts were normal, and the physical exam was unremarkable. CMV, EBV, HSV PCRs, and HIV-1 RNA PCR were negative. While awaiting additional workup, he was started on Pneumocystis jirovecii (PJP) and antifungal prophylaxis with pentamidine and fluconazole, respectively, as well as intravenous immune globulin. Isolation precautions were instituted, and maternal breast milk was initially withheld until maternal CMV resulted negative.
Maternal engraftment studies were negative. T cell proliferation assay with phytohemagglutinin (PHA) was normal. Ultimately, rapid targeted analysis of the genome (rTAG) revealed a heterozygous, paternally inherited variant of uncertain significance (VUS) in FOXN1 (supplemental table), deemed the likely cause of his presentation. Repeat lymphocyte subset enumeration two months later showed persistent T cell lymphopenia: CD3+ 318, CD4+ 184, CD8+ 95.
We herein present a novel heterozygous variant in FOXN1 associated with T cell lymphopenia not yet reported in large population databases (ClinVar, gnomAD). Patients with FOXN1 heterozygous haploinsufficiency have variable clinical presentations and trajectories, though generally, T lymphocyte enumeration and function are thought to improve over time. Our case may assist clinicians who encounter patients with similar phenotypes and demonstrates the value of NBS combined with immunogenetic testing to guide management prior to the onset of potentially fatal infection.
