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.

Suggestive Findings

ETV6 thrombocytopenia and predisposition to leukemia should be considered in individuals with the following clinical and laboratory findings and family history.

Clinical findings

• Absent-to-moderate bleeding tendencies (e.g., menorrhagia, epistaxis, easy bruising, gum bleeding)
• Hematologic malignancies, including:
  • B-cell acute lymphoblastic leukemia (B-ALL), which is the most common
  • Acute myeloid leukemia (AML)
  • Myelodysplastic syndrome (MDS)
  • Myeloproliferative neoplasms (MPN)
  • Mixed phenotype acute leukemia (MPAL)
  • Multiple myeloma
• Possibly solid tumors, especially colorectal cancer

Laboratory findings

• Persistent and unexplained mild-to-moderate thrombocytopenia (platelet counts are often >75x10⁹/L) with typically normal platelet size and occasionally accompanied by a high mean platelet volume
• Normal white blood cell count
• Normal hemoglobin concentration, sometimes with a high mean erythrocyte corpuscular volume (MCV)
• Abnormal bone marrow histology with small hyperchromatic megakaryocytes, disseminated toxic granulations, and dysplastic eosinophils in the absence of frank myelodysplasia

Family history

• One or more relatives with thrombocytopenia, acute leukemia, AND/OR solid tumors (particularly colorectal cancer) consistent with an autosomal dominant inheritance pattern
• Note: Absence of a known family history of thrombocytopenia, acute leukemia or solid tumors does not preclude the diagnosis.

Establishing the Diagnosis

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 (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ETV6 thrombocytopenia and predisposition to leukemia has not been considered may be diagnosed using genomic testing (see Option 2).

Clinical Description

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.

To date, a total of 100 individuals from 26 families have been identified with a germline pathogenic variant in ETV6 [Paulsson et al 2010, Di Paola & Porter 2019, Rampersaud et al 2019, Ross et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

The penetrance of thrombocytopenia in this disorder is thought to exceed 90%.

The penetrance of malignancy, specifically lymphoid and myeloid, is estimated at 30%.

Prevalence

The prevalence of ETV6 thrombocytopenia and predisposition to leukemia is unknown. To date, around 100 individuals have been reported to have this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ETV6 thrombocytopenia and predisposition to leukemia, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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

Individuals with ETV6 thrombocytopenia and leukemia predisposition should adhere to published population-based cancer screening guidelines, including for breast and colon cancers. In addition to education regarding the signs and symptoms of hematologic malignancies, the following surveillance should be considered.

Agents/Circumstances to Avoid

For individuals with ETV6 thrombocytopenia and predisposition to leukemia and a history of bleeding, medications that decrease platelet function (e.g., aspirin, nonsteroidal anti-inflammatories) should be avoided. Similarly, participation in contact sports is not 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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Platelet counts should be monitored during pregnancy and prior to delivery, in collaboration with a hematologist. 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.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

ETV6 thrombocytopenia and predisposition to leukemia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• To date, all individuals diagnosed with ETV6 thrombocytopenia and predisposition to leukemia have inherited an ETV6 pathogenic variant from a heterozygous parent. In some families, the heterozygous parent did not have any known clinical findings associated with ETV6 thrombocytopenia and predisposition to leukemia.
• De novo ETV6 pathogenic variants have not been reported to date in ETV6 thrombocytopenia and predisposition to leukemia.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.

• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with ETV6 thrombocytopenia and predisposition to leukemia may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance of malignancies, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. A sib who inherits the ETV6 pathogenic variant is expected to exhibit mild thrombocytopenia but may never develop leukemia due to the incomplete penetrance of the hematologic malignancies in this syndrome.
• If the ETV6 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the ETV6 pathogenic variant but have no clinical findings of ETV6 thrombocytopenia and predisposition to leukemia, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for the disorder because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with ETV6 thrombocytopenia and predisposition to leukemia has a 50% chance of inheriting the ETV6 pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the ETV6 pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the ETV6 pathogenic variant in the family.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ETV6 has two start codons, one located at exon 1 and one located upstream of exon 3. Although two isoforms have been demonstrated to be expressed at the protein level, the function of the isoforms has not been evaluated. ETV6 encodes transcription factor ETV6. There are three main domains:

• N-terminal pointed domain
• DNA binding domain located at the C terminus
• Linker region

ETV6 is a repressor of transcription, with critical roles in embryonic development and hematopoietic regulation [Hock et al 2004]. ETV6 is highly expressed in hematopoietic progenitor cells and is essential for hematopoiesis in the bone marrow [Di Paola & Porter 2019].

Mechanism of disease causation. Loss of function. The majority of pathogenic germline variants described to date have been located within the DNA binding domain at the C terminus. These are mostly loss-of-function missense variants, but nonsense and frameshift variants have also been identified. Single- and multiexon deletions have also been described and are thought to affect splice sites, resulting in truncation of the protein [Di Paola & Porter 2019].

Cancer predisposition. The molecular basis for predisposition to hematologic malignancy, specifically leukemias, in individuals with ETV6 thrombocytopenia and predisposition to leukemia is not fully understood. Individuals with germline pathogenic ETV6 variants and leukemias were not found to have a somatic hit on the second ETV6 allele, though two cases have been reported with biallelic loss of ETV6 [Topka et al 2015].

Cancer and Benign Tumors

Somatic variants involving ETV6 are the most common type of cytogenetic finding in pediatric B-ALL. Specifically, the ETV6-RUNX1 fusion protein is identified in almost 25% of cases [Hunger & Mullighan 2015]. The other ETV6 allele is often mutated suggesting a tumor-suppressive role for ETV6 [Raynaud et al 1996]. In addition, ETV6 is translocated, often with NTRK3, in several solid tumors including fibrosarcoma, secretory carcinoma of the salivary gland, and breast cancer [Biswas et al 2020].

Revision History

• 19 November 2020 (ma) Review posted live
• 31 January 2020 (bbp) Original submission

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