Monoallelic RUNX1 germline pathogenic variants cause autosomal dominant FPDMM which typically presents with mild-to-moderate thrombocytopenia with normal-sized platelets, a functional platelet defect leading to prolonged bleeding and an increased risk of MDS and AL (more commonly AML, followed by T-ALL).r Approximately 25% of families have at least one individual with a lymphoid malignancy.rr More rarely, other types of leukaemia, including B-cell ALL, hairy cell leukaemia, and chronic myelomonocytic leukaemia, and lymphomas have been reported.r The risk of malignant transformation may be higher in patients with dominant negative variants compared to haploinsufficient variants.r The median age of onset for haematological malignancy is 33 years.r
There is significant clinical heterogeneity in patients with RUNX1-FPDMM. Almost all will develop some degree of abnormal bleeding due to platelet deficiencies. However, there is inter- and intra-familial phenotypic variability and for some individuals it may remain subclinical and undiagnosed. Bleeding abnormalities may include epistaxis, easy bruising, excessive bleeding during minor surgery or injuries, and/or menorrhagia. Age of onset can range from infancy to late adulthood.
Skin findings, including eczema and psoriasis, have been reported in up to 50% of individuals with RUNX1-FPDMM and can be treated topically. An increased frequency of other atopic and autoimmune disorders have been reported, although requires further investigation.r
For individuals with RUNX1-FPDMM who develop MDS or haematological malignancy initial management is determined by the standard of care for the particular diagnosis.
There is no agreed protocol for the management of RUNX1 germline pathogenic variant carriers who have not developed MDS/haematological malignancy.rrr The recommendations in this protocol are based on expert opinion.
Consider referring to a research protocol where available.
Testing for RUNX1 germline pathogenic variants
Somatic genetic rescue (SGR) can lead to loss of a RUNX1 germline pathogenic variant in white blood cell DNA from peripheral blood. Saliva and buccal cell specimens can be contaminated with white blood cells and are not accurate for detection of a RUNX1 germline pathogenic variant. Cultured skin fibroblasts from a skin punch biopsy, or DNA extracted from hair bulbs, are the preferred tissue specimens for germline testing for RUNX1 pathogenic variants.r
If stem cell transplantation is planned, genetic testing of relatives who are potential donors is recommended to prevent haematopoietic stem cell transplantation from a relative who has inherited the familial RUNX1 pathogenic variant. The use of a RUNX1-affected donor has been associated with poor donor and recipient outcome.r
Risk to donor:
Risk to recipient:
- Higher rates of graft failure
- Poor graft function
- Donor derived leukaemia
- Post-transplant lymphoproliferative disease
There is no evidence of benefit of surveillance by periodic FBE, but this is a low-risk procedure and has the potential to detect peripheral blood abnormalities prior to onset of obvious symptoms.r
Bone marrow biopsy has the potential to detect malignant transformation prior to the onset of symptoms. However, this is an invasive procedure, there is incomplete penetrance for haematological malignancy (see Lifetime risk of cancer/haematological features) and there is lack of evidence for a beneficial effect of baseline and/or periodic bone marrow biopsy on neoplasia-related morbidity and mortality. Surveillance by bone marrow biopsy is NOT recommended outside a research protocol.
Asymptomatic carriers of RUNX1 germline pathogenic variants develop detectable clonal haematopoiesis prior to malignant transformation (cumulative risk of up to 80% by age 50 years).r Next generation sequencing to detect clonal haematopoiesis in cells from peripheral blood or bone marrow has the potential to prospectively identify RUNX1 carriers at higher risk for evolution to MDS/AML. However, clinical utility is unproven, and this is NOT recommended outside a research protocol.
There is no evidence to support prophylactic/pre-emptive stem cell transplantation in RUNX1 germline pathogenic variant carriers who have not developed a haematological malignancy.
If stem cell transplantation is planned, genetic testing of relatives who are potential donors is recommended to prevent haematopoietic stem cell transplantation from a relative who has inherited the familial pathogenic variant.
Thrombocytopenia and platelet dysfunction
Most RUNX1 germline pathogenic variant carriers have thrombocytopenia, which is usually mild to moderate.rr Almost all carriers have a functional platelet defect leading to abnormal platelet secretion and function. In some cases platelet transfusion may be required.