Expanding the spectrum of Sideroblastic Anemia with B-cell Immunodeficiency, Periodic Fever and Developmental Delay (SIFD) syndrome: a case report with new clinical insights and novel genetic variant

Abstract

Sideroblastic Anemia with B-cell Immunodeficiency, Periodic Fever and Developmental Delay (SIFD) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the TRNT1 gene, encoding tRNA nucleotidyltransferase 1, an enzyme essential for mitochondrial and cytosolic protein translation. The disease is characterized by a wide phenotypic spectrum, ranging from isolated hematological involvement to multisystem inflammatory disease. Herein, we report a pediatric patient with early-onset sideroblastic anemia, recurrent inflammatory episodes, B-cell immunodeficiency, immune dysregulation (cytopenia refractory to conventional treatment, splenomegaly and chronic interstitial lung disease), ectodermal dysplasia, mild developmental delay with white-matter hypomyelination, and progressive multisystem involvement. Genetic testing identified two biallelic TRNT1 variants, the novel c.841G>C variant and the previously reported pathogenic c.1252dupA variant, inherited from the father and mother, respectively, confirming the diagnosis of SIFD. The patient required immunoglobulin replacement therapy and immunomodulatory treatment, including rituximab, with partial control of infectious and immune dysregulation manifestations. This case expands the clinical, immunological, and genetic spectrum of TRNT1-related disease and highlights that immune dysregulation may dominate the clinical course. SIFD should be considered in children presenting with sideroblastic anemia associated with recurrent unexplained inflammation, B-cell immunodeficiency, cytopenias, and multisystem involvement. Early genetic diagnosis is essential to guide monitoring, therapeutic decisions, and prognostic stratification.