GFI1B mutations define an emerging form of inherited thrombocytopenia: insights from a case report and literature review

Inherited thrombocytopenias (ITs) constitute a heterogeneous group of congenital bleeding disorders caused by defects in over 50 genes that predominantly affect platelet production. GFI1B has recently emerged as a critical transcriptional regulator of megakaryocyte and erythroid differentiation. Its dysfunction underlies a rare autosomal dominant form of IT, which usually results in moderately reduced platelet counts. We report an adult male with lifelong severe thrombocytopenia (platelet count range 10–20 × 10⁹/L) and recurrent bleeding episodes since early childhood. Comprehensive molecular analysis identified a heterozygous NM_001377304.1:c.814 + 1G > A variant in the zinc finger region of GFI1B, resulting in a frameshift and premature truncation. The proband exhibited hallmark features of this IT subtype, including α‑granule deficiency and persistent CD34 expression in megakaryocytes and platelets. Based on preclinical evidence, the patient initially received eltrombopag, followed later by romiplostim, achieving a partial platelet response and improvement in bleeding symptoms. Familial analysis revealed marked variability in platelet counts and bleeding phenotypes among carriers of the same variant, including the patient’s mother, highlighting that clinical outcomes cannot be reliably predicted from genotype alone. A literature review confirmed considerable phenotypic heterogeneity in GFI1B-related thrombocytopenia, indicating that variant type and location only partially account for disease severity. This report represents the first in-human use of thrombopoietin receptor agonists in GFI1B-related thrombocytopenia. It underscores the challenges in diagnosing and managing ITs and emphasizes the importance of early genetic testing. Further studies are needed to elucidate the molecular determinants of phenotypic variability and to develop targeted therapeutic strategies for affected patients.