Clinical characteristics.

ANKRD26-related thrombocytopenia is characterized by lifelong mild-to-moderate thrombocytopenia with a normal platelet size and no syndromic associations. Most individuals have normal hemostasis or a mild bleeding phenotype and do not develop severe spontaneous bleeding. Some individuals may have concomitant erythrocytosis and leukocytosis. The risk for myeloid malignancies (including myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelogenous leukemia) is increased in individuals with ANKRD26 pathogenic variants.

Diagnosis/testing.

The diagnosis of ANKRD26-related thrombocytopenia is established in a proband by the presence of lifelong thrombocytopenia and identification of a heterozygous pathogenic variant in ANKRD26 on molecular genetic testing.

Management.

Treatment of manifestations: Adjunct hemostatic agents (e.g., antifibrinolytics, desmopressin) for bleeding or a major surgical procedure; platelet transfusions are reserved for severe bleeding or procedures with a high bleeding risk.

Prevention of secondary complications: For individuals with a myeloid neoplasm, careful consideration of stem cell transplant eligibility and pre-transplant therapies undertaken through a large academic institution with experience in the management of individuals with germline predisposition syndromes.

Surveillance: Surveillance for early detection of myeloid neoplasms should include an annual complete blood count with bone marrow examination if abnormalities are noted.

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 by evaluation of the platelet count and molecular genetic testing of the ANKRD26 pathogenic variant in the family in order to identify as early as possible those who may benefit from surveillance.

Genetic counseling.

ANKRD26-related thrombocytopenia is inherited in an autosomal dominant manner. All individuals reported to date have an affected parent. Each child of an individual with ANKRD26-related thrombocytopenia has a 50% chance of inheriting the ANKRD26 pathogenic variant. Once the ANKRD26 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible; however, phenotypic variability (due to variable expressivity) within families is observed.

Suggestive Findings

ANKRD26-related thrombocytopenia should be suspected in individuals with the following:

• Lifelong mild-to-moderate thrombocytopenia (<150 x 10⁹/L, confirmed with repeat examination)
• Normal platelet size (mean platelet volume [fL] per reference interval of automated instrument)
• Absent or minimal bleeding tendency
• Family history of thrombocytopenia with an autosomal dominant pattern of inheritance
• Personal or family history of myeloid neoplasms at a young age
• Previous or suspected diagnosis of immune thrombocytopenia (ITP) without improvement on immunosuppressive treatment
• Absence of features suggesting syndromic association

Establishing the Diagnosis

The diagnosis of ANKRD26-related thrombocytopenia is established in a proband by the presence of lifelong thrombocytopenia and identification of a heterozygous pathogenic variant in ANKRD26 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of ANKRD26 should include the 5' untranslated region (5'UTR) to detect known regulatory pathogenic variants. Of note, all individuals diagnosed with ANKRD26-related thrombocytopenia to date have had pathogenic variants identified by ANKRD26 sequence analysis, primarily of the 5'UTR; therefore, the utility of ANKRD26 deletion/duplication analysis is unclear.
• A multigene panel that includes ANKRD26 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included and the sensitivity of multigene panels 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of unknown significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include custom laboratory-designed panels and/or custom phenotype-focused exome analysis. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests (5) The multigene panel should include sequence analysis of ANKRD26 5'UTR.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Individuals with ANKRD26-related thrombocytopenia usually present with lifelong mild-to-moderate thrombocytopenia with a normal platelet size and no syndromic associations. Incidental presentation following routine complete blood count is not uncommon. Some individuals are identified after developing a myeloid neoplasm such as acute myeloid leukemia or myelodysplastic syndrome.

Bleeding history. Most individuals have normal hemostasis or a mild bleeding phenotype and do not develop severe spontaneous bleeding.

Complete blood counts

• Mild to moderate thrombocytopenia (50 to 150 x 10⁹/L) is usually observed. Some individuals can have platelets as low as <10 x 10⁹/L while others have transient correction of thrombocytopenia to >150 x10⁹/L during infectious episodes.
• Platelet size is normal by automated method (mean platelet volume) or microscopic analysis.
• Platelets have normal granularity on light microscopy.
• Individuals can have erythrocytosis, with some presenting with hemoglobin as high as 18.5 g/dL.
• Some individuals have presented with leukocytosis.

Platelet structure and function studies. While abnormal platelet aggregation studies, decreased expression of platelet glycoprotein Ia (GPIa), decreased alpha granules, and increased canalicular network on platelet transmission electron microscopy have been reported, no consistent or definitive structural or functional alterations have been established.

Bone marrow biopsy. On bone marrow biopsy, megakaryocytes are increased in number but small and hypolobated [Noris et al 2011, Perez Botero et al 2015].

Predisposition to myeloid malignancies. The incidence of myeloid malignancies, including myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and chronic myelogenous leukemia, is increased in families with pathogenic variants in ANKRD26, with one series showing an estimated 24-fold increased risk of AML compared to the general population [Noris et al 2013]. Prevalence of AML or MDS among individuals with ANKRD26-related thrombocytopenia is about 8% (see Molecular Genetics, Cancer predisposition).

Genotype-Phenotype Correlations

No consistent genotype-phenotype correlations are known.

Penetrance

Penetrance for thrombocytopenia is complete in individuals with an ANKRD26 pathogenic variant. The risk of transformation to a myeloid malignancy is variable [Noris et al 2013].

Prevalence

The prevalence for this rare disorder is unknown. Fewer than 200 affected individuals have been reported. However, in one large cohort, ANKRD26 5'UTR pathogenic variants appeared to be one of the most frequent causes of inherited thrombocytopenia [Noris et al 2011]. Due to the recent description of this entity and difficulties in diagnosis, the number of affected individuals may be higher.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ANKRD26-related thrombocytopenia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Clinical evaluation by a hematologist and a complete blood count including peripheral smear review for early detection of myeloid neoplasms
• Consideration of bone marrow aspirate and biopsy at initial evaluation to exclude hematologic malignancies if there are other cytopenias, or abnormalities in:
  • Mean corpuscular volume
  • Cell morphology
  • Leukocyte differential
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Most individuals are asymptomatic and undergo observation and surveillance.

When bleeding is present or a major surgical procedure is required, adjunct hemostatic agents such as antifibrinolytics or desmopressin can be given. Platelet transfusions are reserved for severe bleeding or procedures with a high bleeding risk [Balduini et al 2013b].

Thrombopoietin analogs have been used selectively for short periods of time (preoperative). The long-term safety has not been established [Pecci 2013, Fiore et al 2016].

Prevention of Secondary Complications

Once a myeloid neoplasm has been diagnosed, careful consideration of stem cell transplant eligibility and pre-transplant therapies should be undertaken. This is best accomplished at a large academic institution with experience in the management of individuals with germline predisposition syndromes [Babushok et al 2016].

Surveillance

Surveillance for early detection of myeloid neoplasms is indicated in all individuals with ANKRD26-related thrombocytopenia. Guidelines have not been published on the type of testing or frequency of surveillance. A complete blood count on an annual basis with bone marrow examination if abnormalities are noted is commonly recommended.

Agents/Circumstances to Avoid

If a myeloid neoplasm that requires allogeneic stem cell transplantation develops and a related donor is being considered, a donor who does not have the ANKRD26 pathogenic variant present in the family should be used [Godley 2014].

Evaluation of Relatives at Risk

It is appropriate to consider clarifying the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by evaluation of the platelet count and molecular genetic testing of the ANKRD26 pathogenic variant in the family in order to identify those who may benefit from surveillance.

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

Pregnancy Management

Platelet counts and bleeding complications should be monitored during pregnancy. While the thrombocytopenia itself (particularly if mild) is unlikely to affect the pregnancy, low platelet counts can limit the ability to receive epidural analgesia or neuroaxial anesthesia. Strategies to increase platelet count (transfusion) can be considered on an individual basis in consultation with the anesthesiologist.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

ANKRD26-related thrombocytopenia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• To date, all individuals diagnosed with ANKRD26-related thrombocytopenia have an affected parent, either identified by molecular testing or suspected based on pedigree analysis or reported history of thrombocytopenia. The degree of thrombocytopenia varies between and within families, and transient increase in platelet counts during inflammatory events may occur, making molecular genetic testing more accurate than assessment of thrombocytopenia for diagnosis of affected relatives [Noris et al 2011].
• Some individuals diagnosed with ANKRD26-related thrombocytopenia could have the disorder as the result of a de novo ANKRD26 pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of a proband with a pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with ANKRD26-related thrombocytopenia may appear to be negative because of failure to recognize the disorder in family members with very mild thrombocytopenia or transient elevation of platelet counts, or early death of the parent before the onset of symptoms. 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, the risk to the sibs is 50%. Although penetrance of thrombocytopenia is complete, intrafamilial variability in the degree of thrombocytopenia and transient increase in platelet counts during inflammatory events may occur, making molecular genetic testing more accurate than assessment of thrombocytopenia for diagnosis of affected relatives.
• If the parents of the proband have been tested for the ANKRD26 pathogenic variant identified in the proband and a parent has the variant, the risk to the sibs of inheriting the variant is 50%. Penetrance for the thrombocytopenia phenotype is complete with variable severity.
• If the ANKRD26 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is estimated at 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the ANKRD26 pathogenic variant but are clinically unaffected with normal platelet counts on multiple occasions, the risk to the sibs of a proband appears to be low. The sibs of a proband with reportedly unaffected parents in whom confirmatory platelet counts are not available are still at increased risk for ANKRD26-related thrombocytopenia because of the possibility of unrecognized diagnosis in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with ANKRD26-related thrombocytopenia has a 50% chance of inheriting the ANKRD26 pathogenic variant. Molecular genetic testing is recommended for the offspring of a proband with a pathogenic variant as intrafamilial variability in the degree of thrombocytopenia and transient increase in platelet counts during inflammatory events may obscure diagnosis.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the ANKRD26 pathogenic variant, his or her family members may be 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 apparently asymptomatic adult family members requires prior identification of the ANKRD26 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 ANKRD26 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Gene structure. ANKRD26 contains 34 exons, and the longest transcript variant is NM_014915.2 (NC_000010.11). ANKRD26 is thought to be an ancestral member of the POTE gene family [Lee et al 2006]. Alternative transcripts and multiple splice isoforms have been identified. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The great majority of reported pathogenic variants are single-nucleotide substitutions and small deletions located in a 22-nucleotide region within the 5'UTR that contains transcription factor binding sites. A recent report with in vivo and in vitro functional studies suggests the presence of truncating variants outside of the 5'UTR that may lead to predisposition to a myeloid disorder without thrombocytopenia [Marconi et al 2017].

Normal gene product. NM_014915.2 encodes the 1,710-amino-acid protein NP_055730.2. ANKRD26 is a 192-kd protein that contains N-terminal ankyrin repeat domains and C-terminal spectrin helices, which may serve to mediate protein-protein interactions, including with the cytoskeleton. ANKRD26 is expressed in the brain, gastrointestinal tract, liver, adipose, hematopoietic, and reproductive tissues; however, the exact cellular function of ANKRD26 is unknown.

Abnormal gene product. Pathogenic variants in the 5'UTR of ANKRD26 have been shown to disrupt binding of runt-related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) transcription factors. During normal megakaryopoiesis, RUNX1 and FLI1 downregulate expression of ANKRD26. Loss of RUNX1 and FLI1 transcription factor binding leads to overexpression of the ANKRD26 protein in megakaryocytes and defective pro-platelet formation. Accumulation of ANKRD26 in megakaryocytes also increases signaling through the TPO/MPL and MAPK/ERK pathways, which could explain the increased risk of myeloid transformation. Further studies are needed to validate this theory [Bluteau et al 2014].

Cancer predisposition. The molecular basis for the predisposition to myeloid malignancies in individuals with ANKRD26-related thrombocytopenia is unknown. The predisposition is suspected to be related to thrombopoietin hypersensitivity leading to increased proliferation in the context of increased ANKRD26 expression [Balduini et al 2018]. Acquisition of somatic pathogenic variants in epigenetic regulators, transcription factors, and cell cycle regulators has been described at the time of myeloid clonal evolution in individuals with different types of syndromes with germline predisposition to malignancy and is linked to the transformation event [Perez Botero et al 2018].

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Author Notes

Juliana Perez Botero, Stefanie N Dugan, and Matthew W Anderson are part of a multidisciplinary clinical laboratory genetics team that analyzes and interprets results of molecular testing of patients with non-malignant hematologic disorders in the context of the clinical phenotype. From a research standpoint, they focus on generating data to increase the robustness of the phenotype-genotype correlation for specific non-malignant hematologic disorders and generate algorithms for time- and cost-effective molecular diagnosis.

Website: www.versiti.org

Revision History

• 21 June 2018 (sw) Review posted live
• 12 January 2018 (jpb) Original submission