Biallelic STEAP3 Variant in Neonatal Hemophagocytic Lymphohistiocytosis

STEAP3 (Six-transmembrane epithelial antigen of the prostate 3), a metalloreductase, plays a key role in various cell processes, including iron homeostasis, inflammation, and cancer promotion. Over a decade ago, researchers reported a single, heterozygous nonsense variant in STEAP3 linked to transfusion-dependent severe hypochromic anemia. However, a later large population study on STEAP3 found no phenotypic red cell changes in heterozygous individuals. While the genotype and phenotype of STEAP3 are tentatively established for hypochromic microcytic anemia with autosomal dominant inheritance (MIM: 615234), we describe an autosomal recessive form of STEAP3-related neonatal familial hemophagocytic lymphohistiocytosis (HLH). We expanded the phenotype to include cytopenia and neonatal HLH. Our report on two affected male siblings highlights the expanded phenotype, clarifies the phenotypic spectrum of STEAP3, and broadens its genetic inheritance, ultimately providing a clinical and molecular workup for neonatal patients with unexplained HLH.