Runt-related transcription factor 1 (RUNX1), also known as AML1 or core-binding factor subunit α-2 (CBFα2), is a transcription factor that regulates the expression of genes that are necessary for the normal development of hematopoietic stem cells. RUNX1 binds to its heterodimeric partner core binding factor beta (CBFβ) to form a core binding factor, and regulates the expression of various target genes, including hematopoietic differentiation, ribosome biogenesis, cell cycle regulation, p53 and transforming growth factor β signaling pathways . Somatic mutations in
Germline mutations in
A 13-year-old boy presented at our clinic for persistent thrombocytopenia. Blood testing at the age of 10 found that his platelet count was 82,000/μL. After that initial testing, a blood test was performed at a nearby hospital every 6 months, and the platelet count continued to be about 80,000-90,000/μL. Relevant birth history indicated that he was born as a full-term infant by cesarean section, and there was no specific past history. The patient had experienced frequent bruising since childhood and reported similar symptoms recently. His parents and brother did not present with signs of bleeding tendency.
The blood test performed at the first visit at the age of 10 also revealed leukocytes levels of 5,660/μL, hemoglobin 13.0 g/dL, and platelets at 83,000/μL. Prothrom-bin time and partial thromboplastin time were within the normal ranges, and the anti-nuclear antibody and anti-platelet antibody tests were negative. The von Willebrand factor (vWF) antigen test result was 69%, the vWF ristocetin cofactor activity test was 68%, and the β-glucosidase activity was 7.3 nmol/hr/mg (6.0-9.0 nmol/hr/mg). C3, C4 and CH50 levels were normal, and H. pylori antibody was also negative. Platelet function tests and bone marrow study were not performed. Thereafter, follow-up testing values for the platelet count continued indicated in the range of 47,000-87,000/μL.
After follow-up, inherited thrombocytopenia was suspected because the patient continued to experience thrombocytopenia, had a more severe bleeding tendency compared to the platelet count, and had a bleeding tendency similar to that reported in childhood. Diagnostic exome sequencing was performed on the patient at the age of 18. Diagnostic exome sequencing was performed through peripheral blood, and 5,447 target genes were analyzed using a NextSeq 550 System (Illumina, San Diego, USA). DNA sequencing demonstrated a heterozygous mutation of the
Inherited thrombocytopenias have been identified in more than 30 diseases . Inherited thrombocytopenias are caused by germline mutations of genes associated with each step of the platelet production process, which can be divided into three groups . The first step is differentiation and proliferation of hematopoietic stem cells into immature megakaryocytes. The second step is the maturation of immature megakaryocytes. In this stage, DNA accumulates in up to 128N through endomitosis, and a large amount of mRNA and proteins stored in α-granules are produced. The third step is the production of proplatelets and the release of platelets. Transcription factors such as
An important aspect for managing patients with FPD/AML is the high incidence of hematologic malignancies (35-40%). MDS and AML mainly occur, and T-cell acute lymphoblastic leukemia, hairy cell leukemia, and chronic myelomonocytic leukemia have also been reported . According to a recent study, about 30% of hematologic malignancies in FPD/AML patients occurred before the age of 20 . However, a
Inherited thrombocytopenia is a rare disease, and diseases related to early megakaryocyte formation defects or platelet formation and release defects such as congenital amegakaryocytic thrombocytopenia and
In conclusion, the suspicion of hereditary thrombocytopenia is necessary in patients with chronic thrombocytopenia that has persisted since childhood. If inherited thrombocytopenia is suspected, evaluation and considerations for diseases related to megakaryocyte maturation defects, such as FPD/AML, will also be needed.
The authors have no conflict of interest to declare.