Early-Onset TRNT1-Related SIFD Syndrome with an Additional Monoallelic C7 Variant: A Pediatric Case Report
TL;DR
This case highlights the importance of early genetic evaluation in infants with recurrent fever, microcytic anemia, immune abnormalities, and multisystem involvement and emphasizes the need for cautious interpretation of additional monoallelic pathogenic variants detected by broad genetic panels when functional confirmation and a compatible inheritance pattern are lacking.
Abstract
Background and Clinical Significance: Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) syndrome is a rare autosomal recessive disorder caused by biallelic variants in the TRNT1 gene, which encodes tRNA nucleotidyltransferase 1. The disease typically presents early in life with microcytic anemia, recurrent febrile episodes, developmental delay, and immune dysfunction. Because of its rarity and variable clinical expression, diagnosis may be challenging, and broad genetic testing can identify additional variants whose clinical significance requires careful interpretation. Case Presentation: We report a 4-month-old male infant with recurrent febrile episodes, severe recurrent microcytic anemia, recurrent infections, mild psychomotor developmental delay, and multisystem involvement. Genetic analysis identified two heterozygous TRNT1 variants inherited from different parents and confirmed to be in trans: a maternally inherited pathogenic frameshift variant, c.428_431del, p.(Asp143Glyfs12), and a paternally inherited missense variant, c.1246A>G, p.(Lys416Glu), initially classified as a variant of uncertain significance and subsequently interpreted as likely pathogenic in the context of the clinical phenotype and segregation findings. These findings supported the diagnosis of TRNT1-related SIFD syndrome. An additional heterozygous pathogenic C7 variant, c.633_643del, p.(Ser212Hisfs4), was identified. No second pathogenic C7 allele was detected, and functional complement testing was not performed; therefore, complement component 7 deficiency could not be established. Conclusions: This case highlights the importance of early genetic evaluation in infants with recurrent fever, microcytic anemia, immune abnormalities, and multisystem involvement. It also emphasizes the need for cautious interpretation of additional monoallelic pathogenic variants detected by broad genetic panels when functional confirmation and a compatible inheritance pattern are lacking.