Definition

RUNX1 deficiency or familial platelet disorder with associated myeloid malignancy (FPDMM, OMIM #601399) is a genetic disease caused by mutations 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.

Key Data

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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
Heredity Autosomal dominant
Prevalence Unknown
Genotype-phenotype correlation Not clear
Mutations 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
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Diagnosis

Clinical Diagnostics

A RUNX1 mutation 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 RUNX1 mutation can range from mild symptoms to hematological neoplasia (MDS, AML, T-ALL).

Genetic Diagnostics

The diagnosis of “FPDMM” is confirmed by the detection of a RUNX1 gene mutation. 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 mutation (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 RUNX1 mutations.

The severity of hemorrhaging resulting from thrombocytopenia and thrombocyte functional defects varies greatly.

Malignant Hematological Diseases

The risk of malignant transformation to MDS or AML is 30-40%. Patients carrying a RUNX1 mutation with a dominant negative effect are at greater risk than patients with a haploinsufficient RUNX1 mutation.

Various AML French-American-British (FAB) RUNX1 mutation 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 the development of T-ALL.

The average age of onset for MDS or AML is 33, although the age range is more extensive. T-ALL associated with a RUNX1 mutation generally occurs at an earlier stage of life.

Therapeutic Considerations

Treatment of MDS or AML in patients with an RUNX1 mutation 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 a RUNX1 mutational analysis to rule out the possibility of being an asymptomatic carrier of the same genetic syndrome.

Surveillance Recommendations

Surveillance Recommendations

FPDMM patients should be in the care of a center where they can receive adequate hemato-oncological care and genetic counseling.

The following early-detection procedures should be included:

  • Regular clinical examinations (at least annually, and every 3-6 months when there is a higher risk of MDS/AML)

  • Differential blood count (initially every 3-4 months, which can be extended to every 6-12 months with stable findings, and every 2-4 weeks when there are abnormalities)

  • Bone marrow puncture with a morphological, cytogenetic, and molecular genetic examination of the aspirate/biopsy to detect early signs of developing hematological neoplasia (annually, and more often when there are abnormalities in the blood count)

  • FPDMM patients, their families, and their attending physician should be familiar with suspicious clinical symptoms that indicate the development of leukemia.

  • The family history should be updated regularly with regard to neoplasia, cytopenia, and hemorrhaging.

Additional Information

Open Clinical Trials / Registries

Support Groups

Unfortunately, we are as yet unaware of any existing support groups for patients with RUNX1 deficiency. We will add new information as it becomes available.