https://orcid.org/0000-0003-1754-1260
In this issue of Blood, Wahlster et al provide clinical-pathological evidence suggesting that an increase in bone marrow myeloblasts in addition to dysmegakaryopoiesis is a baseline feature of ANKRD26-related thrombocytopenia.1
ANKRD26-related thrombocytopenia, also known as thrombocytopenia 2 (THC2), is one of the relatively more frequent forms of inherited thrombocytopenia.2,3 Affected individuals present autosomal-dominant thrombocytopenia with normal platelet morphology and function. When present, bleeding symptoms are usually mild. Patients with THC2 have an increased risk of developing myeloid neoplasms, with an overall prevalence of progression of 8%.4 Therefore, along with familial platelet disorder with propensity to acute myelogenous leukemia and ETV6-related thrombocytopenia, THC2 is one of the inherited thrombocytopenias with germ line predisposition to hematological malignancies.5
Wahlster and colleagues describe 8 patients with THC2 from 5 unrelated pedigrees exhibiting an increase in bone marrow CD34+ myeloblasts along with dysmegakaryopoiesis in the absence of malignant progression over a median follow-up of 3.5 years. Of note, this bone marrow picture did not associate with cytopenias other than thrombocytopenia, dysplastic features in other lineages other than megakaryocytes, or significant alterations of bone marrow cellularity. Moreover, cytogenetic and molecular screening was negative for somatic clonal abnormalities in all the subjects. In 4 patients with followed-up bone marrows, the CD34+ blast expansion appeared stable over years. Taken together, these observations suggest that this phenomenon represents an intrinsic feature of the genetic disorder rather than a sign of secondary evolution toward myeloid neoplasms.
Because of the limited follow-up, these data, in particular from a prognostic perspective, need to be interpreted with caution. Nevertheless, it is remarkable that the reported individual with the longest follow-up, who had blast counts up to 10% in the bone marrow, remained clinically well and displayed stable blood counts over a period of 10 years.
The report of Wahlster et al unravels a hitherto unreported characteristic of ANKRD26-related thrombocytopenia that has substantial clinical implications for the assessment and surveillance of affected patients. In fact, clinicians should be aware that the peculiar bone marrow signature with increased myeloblasts and dysmegakaryopoiesis, as well as the already reported changes in blood cell counts such as intermittent erythrocytosis or neutrophilic leukocytosis,6,7 may be part of the baseline hematological phenotype of the disease. The evidence of such bone marrow picture still requires further diagnostic workup, including molecular testing for somatic clonal abnormalities, to exclude a myeloid neoplasm, as well as careful clinical surveillance. However, in the absence of additional red flags indicative of progression to a clonal disorder, these bone marrow findings should not per se prompt a diagnosis of myelodysplasia, initiation of cytoreductive treatments, or consideration of hematopoietic stem cell transplantation.
In addition, the article refocuses the attention on a subtle diagnostic pitfall concerning THC2. Patients with inherited thrombocytopenia are often misdiagnosed as having immune thrombocytopenia and may receive unnecessary immunosuppressive treatments including splenectomy.3 Because of dysmegakaryopoiesis and, as now shown, increased blasts in the bone marrow, patients with THC2 have the additional risk of being diagnosed with myelodysplastic syndrome and being treated with inappropriate and possible harmful myelosuppressive agents.8 In this regard, it is well to remember that careful exploration of personal and family history represents a simple tool that is often sufficient to suggest the genetic nature of a thrombocytopenia, which can be eventually confirmed with molecular testing. Furthermore, the myelodysplastic syndrome subtype with thrombocytopenia as the only form of cytopenia and unilineage megakaryocyte dysplasia is very rare.9
In conclusion, the report of Wahlster and colleagues provides new insights into the biology of THC2, which should help clinicians to distinguish baseline hematological phenotype from possible signs of malignant progression, thus improving patients’ clinical management, including the prognostic assessment and the planning of follow-up and counseling. The latter topic is still debated and raises difficult ethical issues.10
The findings by Wahlster et al represent a significant step toward the broader goal of defining the baseline clinical and molecular features of the germ line predisposition syndromes, including the other 2 inherited thrombocytopenias associated with propensity to blood neoplasms, due to mutations in the RUNX1 or ETV6 genes. A better understanding of the biology of these disorders is essential to shed light on the second-hit mechanisms triggering the malignant evolution in these patients, for whom the risk of progression is extremely variable, even within the same family, and currently remains unpredictable.
Research on inherited thrombocytopenias with a propensity to develop hematological malignancies represents a unique opportunity to gain insights into the fascinating field of the early events preceding the development of blood neoplasia.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
