Clinical characteristics: Individuals with ETV6 thrombocytopenia and predisposition to leukemia most often present with a lifelong history of thrombocytopenia, which is usually in the mild to moderate range. No syndromic features or associations are consistently shared across pedigrees. Affected individuals also have a moderate risk of developing a hematologic malignancy (with B-cell acute lymphoblastic leukemia [B-ALL] being the most common) and possibly other malignant solid tumors, particularly colorectal cancer.

Diagnosis/testing: The diagnosis of ETV6 thrombocytopenia and predisposition to leukemia is established in a proband by identification of a heterozygous germline pathogenic variant in ETV6 by molecular genetic testing.

Management: Treatment of manifestations: For clinical bleeding, local measures with consideration of antifibrinolytic agents, desmopressin, and/or platelet transfusion if bleeding is moderate to severe. For neoplasm, standard neoplasm-specific therapy with consideration of indications for stem cell transplantation, eligibility, and available donors.

Prevention of secondary complications: For individuals with a history of moderate or severe bleeding, antifibrinolytic agents or desmopressin may be considered prior to surgical procedures to reduce bleeding complications. Platelet transfusions should be used judiciously, particularly in women of childbearing age, to reduce the risk of alloimmunization.

Surveillance: Complete blood count with differential every six to 12 months and consideration of bone marrow aspirate and biopsy annually. The frequency of such screening must be weighed against the burden of the screening protocol, particularly in young children. The exact frequency of CBC and bone marrow evaluations should be determined on a case-by-case basis by the physician and in consideration of patient/family preferences.

Agents/circumstances to avoid: For those with a history of bleeding, avoidance of medications that decrease platelet function (e.g., aspirin, nonsteroidal anti-inflammatories) and avoidance of participation in contact sports are recommended.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of clinical surveillance for malignancy and management of potential significant thrombocytopenia.

Pregnancy management: Platelet counts should be monitored during pregnancy and prior to delivery. Platelet transfusions prior to invasive procedures (e.g., epidural analgesia or cæsarean section) or at the time of delivery may be considered in those with a history of bleeding or severe thrombocytopenia, on a case-by-case basis.

Genetic counseling: ETV6 thrombocytopenia and predisposition to leukemia is inherited in an autosomal dominant manner. To date, all affected individuals have inherited the ETV6 pathogenic variant from a parent, although in some instances the heterozygous parent did have any known clinical findings. The offspring of an individual with ETV6 thrombocytopenia and predisposition to leukemia are at 50% risk of inheriting the ETV6 pathogenic variant. Once the ETV6 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.