Neonatal-Onset Refractory Thrombocytopenia and Anemia Associated With a Homozygous In-Frame NFE2 Duplication

Objective:Rare disease Background:NFE2 encodes p45/NF-E2, a transcriptional regulator of megakaryocyte maturation and platelet production.However, germline NFE2-associated cytopenias are rare; consequently, the clinical spectrum is incompletely defined. Case Report:We report the case of a preterm neonate born to consanguineous parents who developed day-1-onset bicytopenia with transfusion-dependent thrombocytopenia and intermittent normocytic anemia.Initial evaluation did not support immune-mediated or consumptive causes; moreover, counts were refractory to intravenous immunoglobulin and romiplostim (a thrombopoietin-receptor agonist).Bone marrow examination showed dysmegakaryopoiesis with a paucity of late megakaryocyte forms, supporting defective terminal maturation.Trio sequencing with copy-number analysis identified a homozygous in-frame NFE2 duplication (c.889_900dup; p.Glu297_Arg300dup); both parents were heterozygous carriers, consistent with autosomal-recessive segregation.The duplication lies within the CNC region, adjacent to the basic leucine zipper module implicated in DNA binding and small Maf partner dimerization.Therefore, segregation, domain context, marrow morphology, and TPO-RA non-response implicate NFE2 as the leading etiologic signal, although the variant remains of uncertain significance. Conclusions:This case broadens the emerging NFE2 phenotype to neonatal-onset refractory bicytopenia with dysmegakaryopoiesis and, accordingly, supports a downstream p45/NF-E2 transcriptional maturation defect rather than impaired THPO-MPL signaling.Persistent neonatal cytopenias with dysmegakaryopoiesis and failure of immune-directed therapy and TPO-RA treatment should, therefore, prompt early germline evaluation, ideally trio sequencing with CNV analysis.Finally, targeted functional studies (transactivation, DNA binding, partner interaction) are needed to generate PS3-level evidence and enable definitive reclassification.