3 Discussion
ETV6 -RT, as illustrated by the study of this family, presents with mild and variable clinical manifestations that can easily be overlooked, especially when historical platelet counts and a complete family history are not readily available. Typical platelet counts in patients with ETV6 -RT are in the mild to moderate thrombocytopenia range, usually >75×109/L4,5. Platelet size is normal, and platelet morphology or peripheral smear findings do not show distinguishing features that set it apart from other inherited thrombocytopenias3,5. Mean corpuscular volume can be mildly elevated in patients with ETV6 -RT4,6, and while not specific to this disorder, is a useful clinical clue when present. Bleeding is often variable; impaired platelet aggregation with adenosine diphosphate and arachidonic acid, as well as abnormal alpha granule morphology on PTEM, have been described6. Patients with ETV6-RT can exhibit megakaryocytes that are small and hypolobulated4,6,7, as in the case of patient B. The inheritance pattern is autosomal dominant, and the penetrance of the thrombocytopenic phenotype is complete. The family’s history showed affected family members in multiple generations, with males and females affected equally, supporting this inheritance pattern.
When the clinical evaluation of a patient and their family is suggestive of an inherited thrombocytopenia without pathognomonic clinical features, genetic testing becomes an essential tool in confirming the diagnosis and providing appropriate genetic counseling. At least three nonsyndromic autosomal dominant inherited thrombocytopenias with normal platelet size are associated with hematologic malignancy and involve variants in RUNX1 , ANKRD26 andETV68-10 . Genetic testing is the only strategy able to confidently distinguish them from each other, which is an important step in the clinical approach because the expected rate of evolution to malignancy and type of associated neoplasm varies between them. ETV6 -RT has an overall 30% risk for hematologic malignancies—including B-cell acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, and colon cancer4,11-13.
Results of genetic testing can be difficult to interpret, especially in cases where the identified variant is novel. In absence of prior reports in the literature or functional evidence to support its pathogenicity, other evidence—including thorough knowledge of the functional domains of the protein affected, population data, and in silicoprediction tools—are helpful in variant classification. However, due to insufficient evidence, frequently the classification is VUS, which is not clinically actionable14. As illustrated in this family, segregation can provide key additional evidence for variant classification and resolution of the VUS.
Inherited thrombocytopenias with mild decrease in platelet counts and no syndromic associations, such as ETV6 -RT, are challenging to diagnose due to their non-specific clinical presentation and low frequency compared to acquired platelet disorders. Recognizing the clinical clues of inherited thrombocytopenia is an important diagnostic skill to prevent misdiagnosis and ensure proper counseling regarding risk of malignancy. Gathering a complete family history is essential in this process. An initial stepwise approach helps rule out the most frequent causes of thrombocytopenia. Special attention to family history, genetic testing, and family studies using multidisciplinary clinical and laboratory-based teams can facilitate confirmation of an inherited thrombocytopenia diagnosis, even when limited variant-specific data is available.