ETV6 Deficiency – Definition
ETV6 deficiency or thrombocytopenia 5 (OMIM #616216) is a genetic disease caused by pathogenic variants in the ETV6 gene. It is characterized by mild to moderate thrombocytopenia with or without a tendency to bleed, macrocytosis, and an increased risk of developing acute leukemia (especially B-ALL), myelodysplastic syndrome (MDS), and – more rarely – solid tumors.
Synonyms:
TEL deficiency, thrombocytopenia 5 with a predisposition to malignancy
Gene:
ETV6 (also TEL)
Gene product:
ETV6
Function:
Transcription factor that plays an important role in hematopoiesis and embryonic development
Pattern of inheritance:
Autosomal dominant
Prevalence:
Approximately 1% of B-ALL occur during childhood
Genotype-phenotype correlation:
Nearly all mutations occur in the ETS domain, which mediates DNA binding
Penetrance:
Approximately 25% develop acute leukemia and/or MDS.
ETV6 Deficiency – Diagnosis
Diagnosis
A pathogenic variant in the ETV6 gene should be suspected and genetically tested whenever there is a pronounced familial incidence of mild to moderate thrombocytopenia or whenever there is a combination of thrombocytopenia, leukemia, or a solid tumor.
Genetic Diagnostics
The diagnosis of “ETV6 deficiency” is confirmed by detecting a mutation in the ETV6 gene.
Differential Diagnoses
- Thrombocytopenia of other causes
- Hematologic neoplasms with another underlying pathogenic variant (e.g., RUNX1)
Clinical Presentation
Thrombocytopenia
- Mild to moderate thrombocytopenia usually occurs in thrombocytes of normal size.
- There is not always a tendency to bleed; it is usually mild to moderate, with a severe tendency to bleed occurring only rarely. Symptoms are usually epistaxis, bleeding gums, increased bruising, and menorrhagia.
- Thrombocytopenia and a tendency to bleed may already manifest during infancy.
Hematological Diseases
- Pre-B-All is the most common hematological malignancy, with an average onset at 7 years of age observed to date (age range of 2-37 years). However, cases of myeloid malignancy such as MDS, AML, and chronic myelomonocytic leukemia (CMML) have also been described.
- Most patients have normal hemoglobin, and MCV is generally normal or elevated.
- The bone marrow frequently exhibits immature hypolobated megakaryocytes, mild dyserythropoiesis, and mild nuclear hypolobation and hypogranulation of myeloid cells.
Additional Manifestations
- In some patients, early-onset colorectal carcinomas have been reported.
- The following tumors have been reported in a few cases: fibroadenoma of the breast, meningioma, mammary carcinoma, duodenal adenocarcinoma, and renal cell carcinoma.
Special Features of Treatment
- Mild to moderate thrombocytopenia without a tendency to bleed generally does not require any treatment. During childbirth or major operations, thrombocyte concentrates should be available and administered if there is heavy bleeding.
- Treatment of MDS or leukemia in patients with an ETV6 mutation should be discussed thoroughly with the corresponding study centers.
- When a stem cell transplant is planned with an HLA-compatible sibling as the donor, he or she should first undergo a pathogenic variant in the ETV6 gene analysis to rule out the possibility of being an asymptomatic carrier of the same genetic syndrome.
Diagnosis of ETV6 DeficiencyWhat's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of ETV6 Deficiency - What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Patients with ETV6 deficiency should be referred to a specialized center where they can receive appropriate hematological-oncological care and genetic counseling.
The following should be included in the screening measures:
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Regular clinical examinations: at least annually; for higher risk of MDS/AML, every 3–6 months.
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Differential blood count including reticulocytes: every 6–12 months.
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Bone marrow aspiration and biopsy: every 1 to 3 years, depending on biopsy findings.
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ETV6-deficient patients, their families, and their treating physicians should be familiar with clinical symptoms indicative of developing leukemia.
- The family medical history should be regularly updated concerning neoplasms, cytopenias, and bleeding tendencies
