<i>THPO</i> promoter mutation: a familial study on congenital amegakaryocytic thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome, which is characterized by a severe thrombocytopenia at birth without predictive stigmata and by a risk for progression into aplastic anaemia and myeloid malignancy. While CAMT primarily arises from mutations in the <i>MPL</i> gene, recent discoveries have linked biallelic <i>THPO</i> mutations to some CAMT cases. In addition, loss of function monoallelic mutations in this gene have been identified as causing benign autosomal dominant thrombocytopenia. In this study, we report a case of CAMT linked to a homozygous mutation in the promoter region of <i>THPO</i> (c.-324C>T, NM_000460.4). computational analysis indicates that this mutation suppresses the binding of some essential transcription factors to the <i>THPO</i> promoter. Family segregation analysis shows a significant reduction in platelet counts among carriers of the mutation. Our patient received allogeneic haematopoietic stem cell transplantation (HSCT) from her HLA-matched sister (MSD), who carries the mutation. After allogeneic HSCT, the patient showed 100% full donor chimerism, but 1 year after HSCT, despite full donor chimerism, the patient did not complete recover from platelet count, and she has received romiplostim several times. Understanding the MPL-THPO pathway is vital for managing CAMT, emphasizing the importance of identifying and assessing patients' mutations for tailored treatment.