RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies

Clinical characteristics: RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM) is characterized by prolonged bleeding and/or easy bruising and an increased risk of developing a hematologic malignancy. RUNX1-FPDMM is characterized by thrombocytopenia with normal platelet size; bleeding is often greater than expected due to qualitative platelet dysfunction. Myeloid malignancies are the most common, including acute myelogenous leukemia (and myelodysplastic syndrome. T- and B-cell acute lymphoblastic leukemias and lymphomas have also been reported, as well as skin manifestations (e.g., eczema, psoriasis).

Diagnosis/testing: The diagnosis of RUNX1-FPDMM is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in RUNX1 identified by molecular genetic testing.

Management: Treatment of manifestations: Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) in instances of surgeries, injuries, or dental treatments; platelet transfusions may be used for severe bleeding or procedures with a high bleeding risk. Allogenic stem cell transplantation may be considered in individuals with early signs of malignancy and hematopoietic stem cell transplant may be used to treat myelodysplasia; however, recommendations regarding the indications and timing of stem cell transplant can vary. Emollients and topical steroids as needed for eczema; consider providing a medical letter for the school explaining easy bruising; consider use of a medical alert bracelet.

Surveillance: Clinical examination for signs/symptoms of neoplasm (e.g., constitutional symptoms such as fatigue, unexplained fever, unexplained weight loss, shortness of breath) every six to 12 months. Complete blood count with differential every three to four months; bone marrow examination if constitutional symptoms and/or abnormalities on complete blood count are identified; skin exam as needed.

Agents/circumstances to avoid: Medications that affect platelet function (e.g., NSAIDs and antiplatelet agents), activities with a high risk of trauma (e.g., high-risk contact sports), unnecessary radiation, and smoking.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance for malignancy and more targeted medical management.

Genetic counseling: RUNX1-FPDMM is inherited in an autosomal dominant manner. Most individuals diagnosed with RUNX1-FPDMM inherited the causative pathogenic variant from a parent who may or may not have recognized manifestations of the disorder. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. If the RUNX1 pathogenic variant identified in the proband is not detected in parental DNA, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility either of a false negative result in a parent (due to preferential loss of the chromosome with the RUNX1 pathogenic variant), or of parental germline mosaicism. Once the RUNX1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.