Etv6 Thrombocytopenia And Predisposition To Leukemia
Summary
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.
Diagnosis
ETV6 thrombocytopenia and predisposition to leukemia is a nonsyndromic genetic disorder of thrombocytopenia and high risk of leukemia without any other known congenital anomalies. Formal clinical diagnostic criteria have not been published.
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).
Option 1
When the clinical and laboratory findings suggest the diagnosis of ETV6 thrombocytopenia and predisposition to leukemia, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of ETV6 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes ETV6 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. It is important to note that: (1) The genes included in panels and the diagnostic sensitivity of the testing for each gene vary by laboratory and are likely to change over time; (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview and some panels may not include this gene; (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician; and (4) The methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of ETV6 thrombocytopenia and predisposition to leukemia is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Note: A diagnosis of ETV6 thrombocytopenia and predisposition to leukemia should not be confused with individuals who have malignancies with somatic chromosome rearrangements involving ETV6 (see Genetically Related Disorders and Cancer and Benign Tumors).
Table 1.
Molecular Genetic Testing Used in ETV6-Related Thrombocytopenia and Predisposition to Leukemia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ETV6 | Sequence analysis 3 | 23/26 4 |
| Gene-targeted deletion/duplication analysis 5 | 2/26 6, 7 | |
| Karyotype | 1/26 8 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Di Paola & Porter [2019]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Paulsson et al [2010] reported one affected individual with an intragenic deletion involving exon 2.
- 7.
Ross et al [2019] described a family in which individuals had a contiguous gene deletion that included ETV6. Rampersaud et al [2019] reported a germline 75-base-pair deletion of ETV6 at the intron 6-exon 7 junction in all affected individuals. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Ross et al [2019]) may not be detected by these methods.
- 8.
Järviaho et al [2019] described a pedigree in which two second-degree relatives developed B-ALL and were found to have a constitutional, balanced translocation involving ETV6 (t(12;14)(p13.2;q23.1). An additional seven family members were found to harbor the same translocation but did not have a history of leukemia. No family members had thrombocytopenia.
Clinical Characteristics
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.
Thrombocytopenia
Thrombocytopenia is found in more than 90% of affected individuals at the time of diagnosis. However, most affected individuals have normal hemostasis or only a mild bleeding tendency.
Bleeding history
- Most affected individuals do not develop severe spontaneous bleeding episodes.
- Reported bleeding symptoms have included menorrhagia, epistaxis, easy bruising, and gum bleeding [Hock & Shimamura 2017].
Complete blood counts
- Most reported platelet counts are between 100-150x109/L.
- Some affected individuals have platelet counts as low as 32x109/L, but severe thrombocytopenia (<20 x 109/L) is rarely seen without concurrent myelodysplastic syndrome.
- Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume.
Platelet structure and function studies. While abnormal platelet aggregation studies have been observed in a few individuals, no abnormal pattern on platelet membrane receptor distribution has been observed to date. Platelets have also shown abnormal clot retraction and spreading on fibrinogen surfaces [Poggi et al 2017, Di Paola & Porter 2019].
Bone Marrow Biopsy
Bone marrow aspirates in those without concurrent leukemias have revealed dyserythropoiesis, megakaryocyte hyperplasia, and small hypolobulated megakaryocytes [Di Paola & Porter 2019].
Lymphoid and Myeloid Malignancies
About 30% of individuals with ETV6 thrombocytopenia and predisposition to leukemia develop a hematologic malignancy.
- Reported age range at time of diagnosis of a hematologic malignancy is between two and 82 years, with an average and median age of onset of 22 and 11 years, respectively [Di Paola & Porter 2019].
- About two thirds of affected individuals who develop a hematologic malignancy will have B-cell acute lymphoblastic leukemia.
- Other reported malignancies:
- Other forms of acute lymphoblastic leukemia
- Myelodysplastic syndrome (MDS)
- Acute myeloid leukemia (AML)
- Mixed phenotype acute leukemia
- Diffuse large B-cell lymphoma
- Polycythemia vera
Children with ETV6 thrombocytopenia and predisposition to leukemia may be more likely to have hyperdiploid leukemia and be older at the time of diagnosis of leukemia than sporadic cases of leukemia [Moriyama et al 2015]. There is currently no evidence that the presence of a heterozygous germline ETV6 pathogenic variant influences response to therapy, nor are there any recommendations to alter standard therapy based on the presence of a heterozygous germline ETV6 pathogenic variant.
Solid Tumors
There may be an increased risk for the development of solid tumors in those with ETV6 thrombocytopenia and predisposition to leukemia. While the exact risk has not been defined, at least seven molecularly confirmed individuals have a reported history of malignant solid tumors diagnosed before age 50 years, including two with colorectal cancer [Di Paola & Porter 2019].
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.
Differential Diagnosis
Table 2.
Genes of Interest in the Differential Diagnosis of ETV6 Thrombocytopenia and Predisposition to Leukemia
| Gene | Disorder 1 | Associated Malignancies | Hematologic Findings |
|---|---|---|---|
| ANKRD26 | ANKRD26 thrombocytopenia | MDS/AML AUL CLL CML | Thrombocytopenia |
| CYCS | Thrombocytopenia 4 (OMIM 612004) | None | Thrombocytopenia w/normal-sized platelets |
| FLI1 | Bleeding disorder, platelet type 21 (OMIM 617443) | None | Thrombocytopenia w/large platelets |
| RUNX1 | Familial platelet disorder w/predisposition to acute myelogenous leukemia (OMIM 601399) | MDS/AML T-ALL Hairy cell leukemia | Thrombocytopenia (can have normal platelet counts) |
AML = acute myeloid leukemia; AUL = acute undifferentiated leukemia; CLL = chronic lymphocytic leukemia; CML = chronic myeloid leukemia; MDS = myelodysplastic syndrome; T-ALL = T-cell acute lymphoblastic leukemia
- 1.
Disorders in this table are inherited in an autosomal dominant manner.
Management
Expert and consensus clinical guidelines for the management of inherited thrombocytopenia and leukemia predisposition syndromes, including those with germline ETV6 pathogenic variants, have been proposed [Porter et al 2017, Dupuis & Gachet 2018].
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.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with ETV6 Thrombocytopenia and Predisposition to Leukemia
| System/Concern | Evaluation | Comment |
|---|---|---|
| Hematologic/ Oncologic | CBC w/differential | Incl peripheral smear for detection of hematologic neoplasms |
| Consider platelet aggregation studies. | If available & platelet count allows | |
| Consider bone marrow biopsy & aspirate. | Particularly if cytopenias are present on CBC | |
| Consider referral to hematologist/oncologist. | Consider referral to a center w/expertise in predisposition to malignancy, as a multidisciplinary team may help refine optimal management. | |
| Genetic counseling | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling, ideally in a center w/experience in predisposition to hematologic malignancy |
CBC = complete blood count
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with ETV6 Thrombocytopenia and Predisposition to Leukemia
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Clinical bleeding | Local measures | |
| Antifibrinolytic agents; desmopressin | If bleeding is moderate or severe | |
| Platelet transfusion | For acute, moderate-to-severe bleeding 1 | |
| Neoplasm | Standard neoplasm-specific therapy | Consider indications for stem cell transplantation, eligibility, & available donors. Confirm by targeted molecular genetic testing that potential related donors do not have ETV6 thrombocytopenia w/predisposition to leukemia. 2 |
- 1.
Dupuis & Gachet [2018]
- 2.
Godley [2014]
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.
Table 5.
Recommended Surveillance for Individuals with ETV6 Thrombocytopenia and Predisposition to Leukemia
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Hematology/ Oncology | CBC w/differential | Every 6 to 12 mos 1, 2, 3 |
| Bone marrow aspirate & biopsy 4 | Annually 1, 2 |
CBC = complete blood count
- 1.
The benefit of this screening regimen is currently unknown.
- 2.
The frequency of such screening must be weighed against the burden of the screening protocol, particularly in young children. The 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.
- 3.
If changes in the CBC with differential are persistent for 2-4 weeks, particularly cytopenias, consider an additional bone marrow aspirate and biopsy.
- 4.
To include morphology, cytogenetics, fluorescence in situ hybridization (FISH) (e.g., for chromosomes 5q, 7q, 8, and 20q) and molecular studies (depending on morphology, cytogenetics, and/or FISH) [Di Paola & Porter 2019].
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.