RUNX1 Deficiency – Definition
RUNX1 deficiency or familial platelet disorder with associated myeloid malignancy (FPDMM, OMIM #601399) is a genetic disease caused by pathogenic variants in the RUNX1 gene. Characteristic features include thrombocytopenia, thrombocytopathy with a prolonged bleeding time, and an increased risk of developing myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or acute T-cell leukemia (T-ALL). The clinical presentation is heterogeneous.
Synonym:
familial platelet disorder with associated myeloid malignancy (FPDMM)
Gene:
RUNX1
Gene product:
RUNX1 (runt-related transcription factor 1) and
AML1 (acute myeloid leukemia 1) and
CBFA2 (core-binding factor subunit alpha-2)
Function:
Transcription factor that regulates the differentiation of hematopoietic cells in adult stem cells
Pattern of inheritance:
Autosomal dominant
Prevalence:
Unknown
Genotype-phenotype correlation:
Not clear.
Pathogenic variants with a dominant negative effect (missense mutations in the RUNT homology domain, nonsense and frameshift mutations in the C-terminal domain) exhibit an increased risk of MDS/AML.
Deletions may be associated with a syndromic phenotype (contiguous gene syndrome).
Penetrance:
Very variable overall, 30-40% for MDS/AML
RUNX1 Deficiency – Diagnosis
Clinical Diagnostics
A pathogenic RUNX1 variant is suspected in individuals with persisting thrombocytopenia or aspirin-like thrombocytopathy when no other causes have been substantiated. Moreover, there may be indications in the family history, whereby it must be borne in mind that the clinical presentation of a pathogenic RUNX1 variant can range from mild symptoms to hematological neoplasia (MDS, AML, T-ALL).
Genetic Diagnostics
The diagnosis of “FPDMM” is confirmed by detecting a pathogenic RUNX1 gene variant. Large deletions can be detected most easily using CGH or SNP arrays.
Differential Diagnoses
- Thrombocytopenia/thrombocytopathy with a different cause
- Myeloid neoplasia with a different underlying pathogenic variant (e.g. ANKRD26 ETV6)
Clinical Presentation
Thrombocytopenia and Thrombocytopathy
Mild to moderate thrombocytopenia along with low-normal to normal thrombocyte numbers are possible. Thrombocytopenia is due to disrupted maturation of the megakaryocytes. Dysmegakaryopoiesis is the most common abnormal finding in bone marrow smears.
Thrombocyte size is normal. However, there is a functional defect in most cases, with the most common form being dense-granule storage pool deficiency, a reduction in the dense granules that disrupts the irreversible thrombocyte aggregation. However, other functional defects have also been associated with pathogenic RUNX1 variants.
The severity of hemorrhaging resulting from thrombocytopenia and thrombocyte functional defects varies greatly.
Malignant Hematologic Diseases
The risk of malignant transformation to MDS or AML is 30-40%. Patients carrying a pathogenic RUNX1 variant with a dominant negative effect are at greater risk than patients with a haploinsufficient RUNX1 pathogenic variant.
Various AML French-American-British (FAB) RUNX1 pathogenic variant subtypes have been observed. Refractory anemia with excess blasts, chronic myeloid leukemia, and hypoplastic MDS with myelofibrosis occur with MDS and myeloproliferative neoplasms (MPN). In addition to predominantly affecting the myeloid lineage, it is also possible that the lymphatic lineage is affected, which manifests in T-ALL development.
The average age of onset for MDS or AML is 33, although the age range is more extensive. T-ALL associated with a pathogenic RUNX1 variant generally occurs at an earlier stage of life.
Special Features of Treatment
Treatment of MDS or AML in patients with a pathogenic variant in RUNX1 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 an analysis in pathogenic variant RUNX1 to rule out the possibility of being an asymptomatic carrier of the same genetic syndrome.
Diagnosis ofRUNX1 Deficiency- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of RUNX1 Deficiency - What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
FPDMM patients should be linked to a center where they can receive appropriate haemato-oncological care and genetic counseling.
The following early-detection procedures should be included:
- Regular clinical examinations
- CBC including reticulocytes every 6-12 months
- Bone marrow aspiration and biopsy and somatic gene panel every 1-3 years (depending on biopsy results)
- FPDMM patients, their families, and their attending physicians should be aware of suspicious clinical symptoms that may indicate the development of leukaemia.
- Family history should be regularly updated for neoplasia, cytopenias and bleeding
