Ankrd26-Related Thrombocytopenia
Summary
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.
Diagnosis
ANKRD26-related thrombocytopenia is a nonsyndromic congenital thrombocytopenia disorder lacking pathognomonic features and thus requiring molecular confirmation of a heterozygous ANKRD26 pathogenic variant to establish a diagnosis. Formal diagnostic criteria have not been published.
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.
Table 1.
Molecular Genetic Testing Used in ANKRD26-Related Thrombocytopenia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ANKRD26 | Sequence analysis 3, 4 | 42 of 42 reported probands 5 |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 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.
Must include sequencing of 5'UTR, which has a significant number of the known pathogenic variants
- 5.
Al Daama et al [2013], Noris et al [2013], Marquez et al [2014], Ouchi-Uchiyama et al [2015], Perez Botero et al [2015], Averina et al [2017], Ferrari et al [2017], Marconi et al [2017]
- 6.
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.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
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.
Differential Diagnosis
Due to the clinical and genetic heterogeneity and low incidence of inherited platelet disorders, the diagnosis is challenging, and sometimes inherited platelet disorders are misdiagnosed as idiopathic thrombocytopenic purpura (immune thrombocytopenia; ITP). Complex diagnostic algorithms have been proposed [Balduini et al 2013a].
Table 2.
Disorders to Consider in the Differential Diagnosis of ANKRD26-Related Thrombocytopenia
| Disorder | Gene(s) | MOI | Clinical Features | |
|---|---|---|---|---|
| Overlapping | Distinguishing | |||
| Familial platelet disorder w/predisposition to acute myelogenous leukemia (FPD/AML; OMIM 151385) | RUNX1 | AD | Nonsyndromic thrombocytopenia w/normal platelet size & predisposition to myeloid neoplasms | FPD/AML:
|
| ETV6-related thrombocytopenia (thrombocytopenia-5, ETV6-RT) | ETV6 | AD | Nonsyndromic thrombocytopenia w/normal platelet size & predisposition to myeloid neoplasms | ETV6-RT:
|
| CYCS-related thrombocytopenia (thrombocytopenia-4, CYCS-RT; OMIM 616216) | CYCS | AD | Nonsyndromic thrombocytopenia w/normal platelet size | CYCS-RT: Does not predispose to neoplasms |
| Immune thrombocytopenia (ITP) | NA | NA | Thrombocytopenia w/normal (or mildly elevated) platelet size, minimal bleeding unless thrombocytopenia is severe | ITP:
|
AD = autosomal dominant; MOI = mode of inheritance; NA = not applicable; RT = related thrombocytopenia
Management
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.