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.