Last updated:
9/10/2024
Years published: 2018, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Amy Trottier, MD, Department of Hematology, University of Calgary, and the RUNX1 Research Program for the preparation of this report.
Summary
Familial platelet disorder with associated myeloid malignancy (FPD/AML) is a very rare disorder characterized by mild to moderately low platelet count (thrombocytopenia), abnormal platelet function and an increased risk of developing other blood disorders or cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
FPD/AML is caused by changes (variants) in the RUNX1 gene. The RUNX1 gene was previously known as AML1 or CBFA2. FPD/AML is an inherited disorder, meaning that the RUNX1 gene variant is passed down (inherited) from an affected parent such that patients with FPD/AML are born with the disease-causing gene variant.
Platelets are a type of blood cell that help to stop bleeding. Because platelets can be low or not function properly in FPD/AML, patients can have symptoms of easy bruising and bleeding. The severity of symptoms can vary a lot between patients with FPD/AML. Some patients may have no problems with bleeding or bruising whereas other patients may seek medical attention for these reasons. All patients with FPD/AML have a high risk (35-40%) of developing MDS and/or AML in their lifetime; both of which are potentially life-threatening conditions without treatment. The average age of onset of MDS or AML is 33 years. Symptoms of MDS or AML may include tiredness (fatigue), weakness, shortness of breath and frequent infections.
Introduction
Symptoms of FPD/AML were first described in several members of a multigenerational family in 1969. In 1999 it was discovered that inherited (germline) variants in the RUNX1 gene, located on chromosome 21, cause FPD/AML.
FPD/AML is a genetic condition that can affect the way the blood clots and increase the risk of certain blood cancers. People with FPD/AML often have problems with bleeding and bruising because their platelets—tiny cells in the blood that help stop bleeding—are either low in number or don’t work properly. Platelets are made in the bone marrow by cells called megakaryocytes. Note that not everyone with FPD/AML will have all the symptoms described below, and that some people might only have a slight decrease in their platelet count and might not have any noticeable bleeding. The severity can vary widely from person to person, even within the same family. Symptoms may include:
In addition to the bleeding problems, people with FPD/AML have a higher risk—about 35%-40% over their lifetime– of developing certain types of blood cancers, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
MDS is a condition where the bone marrow doesn’t produce enough healthy blood cells. Symptoms can include feeling very tired, weakness, bruising easily and having frequent infections.
AML is a fast-growing cancer of the blood and bone marrow (the internal part of the large bones of the body that produces the blood cells). Symptoms of AML may include low blood counts, fatigue, shortness of breath, unusual bleeding or bruising, swollen gums, fevers, night sweats, weight loss and frequent infections.
Some people with FPD/AML might develop other blood cancers like T- or B-cell acute lymphoblastic leukemia and lymphomas, as well as skin conditions like eczema or psoriasis.
FPD/AML is caused by inherited changes (variants) in the RUNX1 gene, located on chromosome 21. The RUNX1 gene is responsible for production of the RUNX1 protein.
The RUNX1 protein is an important regulator of normal blood cell production (hematopoiesis). Variants in the RUNX1 gene can lead to a decrease in or altered function of the RUNX1 protein, which can result in symptoms of low platelets, impairment of platelet function and a significantly increased risk of developing MDS and/or AML. There are many different variants in the RUNX1 gene that can cause FPD/AML, and most families affected by this condition carry a unique variant that is different from other families with this same disorder. The way in which variants in RUNX1 cause a decrease in platelets and predispose patients to MDS and AML is not yet fully understood.
FPD/AML follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Spontaneous (de novo) gene variants are variants that occur in the egg or sperm cell and are not inherited from the parents.
FPD/AML is a very rare disorder with an unknown incidence and prevalence. To date, as in 2024, more than 130 individuals with FPD/AML have been reported in the medical literature. Patients with FPD/AML have a lifetime risk of approximately 35%-40% of developing MDS and/or AML. The average age of onset of MDS or AML is 33 years, but it has also occurred in patients as young as 6 years and as old as 77 years. Males and females seem to be equally affected and people from all races can be affected.
The diagnosis of FPD/AML is made based on careful evaluation and testing. Doctors suspect this condition based on specific symptoms, lab results, or a family history of related issues. The diagnosis is confirmed through genetic testing that detects variants in the RUNX1 gene. If someone is diagnosed with AML or MDS at a young age, especially if they have a history of low or abnormally functioning platelets or a family history of blood cancers, they may be referred for specialist evaluation and genetic testing.
FPD/AML should be suspected based in the following symptoms:
If FPD/AML is suspected, the doctor will thoroughly review the personal and family history of bruising, bleeding, low platelet counts and any family history of similar issues or blood cancers and will order some laboratory testing, including:
Genetic testing performed on a sample (biopsy) from the bone marrow, saliva, hair, or skin can confirm the diagnosis. The preferred tissue source is a skin biopsy, which can be taken at the time of the bone marrow biopsy or through a punch biopsy, where a small tube-shaped portion of skin is removed.
If a RUNX1 gene variant is confirmed, the affected person may be referred to a genetic counselor.
Treatment
People with FPD/AML usually need to be seen by several medical professionals including general practitioners or primary care physicians, physicians who specialize in cancer (medical oncologists) or blood and bone marrow disorders (hematologists), genetics experts (medical geneticists or genetic counselors), nurses, pharmacists and/or other health care professionals.
At present, there are no specific treatments available for patients with FPD/AML, however people affected with this disorder who have severe bleeding problems should avoid medications that impair platelet function, such as nonsteroidal anti-inflammatories (NSAIDs) and should check with their pharmacist or doctor before starting a new medication or taking a non-prescription medication or supplement. Patients may require platelet transfusions if they have severe bleeding or a very low platelet count prior to a surgery or procedure. Most surgeries can be performed safely with a platelet count greater than 50,000 per microliter of blood.
For people who have developed AML or MDS, treatment is directed for that disorder. (For more information on treatment of these disorders, choose the specific disorder name as your search term in the Rare Disease Database and scroll down to the “Treatment” section.)
The only potential cure for patients who develop MDS is an allogeneic stem cell transplant, a type of bone marrow transplant. In an allogeneic stem cell transplant, hematopoietic stem cells (cells that can make red cells, white cells and platelets) are typically donated from a closely matched sibling family member or unrelated donor and infused into the affected patient after receiving high doses of chemotherapy with or without radiation. Allogeneic stem cell transplant is also commonly used in the treatment of AML. For FPD/AML patients who require an allogeneic stem cell transplant, it is important to perform genetic testing on their siblings for RUNX1 variants prior to using them as a donor because they may carry the same inherited gene variant. If the sibling has a RUNX1 variant, they should not be used as a donor. If they are used as a donor it can result in poor outcomes such as failure of the transplant (engraftment failure) and future development of leukemia or MDS arising from the donor’s cells.
For individuals with FPD/AML, regular monitoring is important and is based on expert guidelines. This typically involves blood tests, including a complete blood count (CBC) with differential, which should be done once or twice a year. A physical exam is also recommended during these visits.
When someone is first diagnosed with FPD/AML, it’s advised that they have a bone marrow evaluation. This test might be repeated if there are any changes in their blood counts or if new health concerns, like frequent infections, arise.
Although yearly bone marrow evaluations are sometimes suggested for research purposes, there’s currently no test that can accurately predict whether someone with FPD/AML will develop blood-related cancers. Therefore, these bone marrow evaluations are not always a standard part of regular care.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
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For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Hayashi Y, Harada Y, Huang G, Harada H. Myeloid neoplasms with germ line RUNX1 mutation. Int J Hematol. 2017;106:183-188.
Morgan N V, Daly ME. Gene of the issue: RUNX1 mutations and inherited bleeding. Platelets. 2017;28(2):208-210.
Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood. 2017;129(15):2070-2082.
University of Chicago Hematopoietic Malignancies Cancer Risk Team. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood. 2016;128(14):1800-1813.
Owen C. Insights into familial platelet disorder with propensity to myeloid malignancy (FPD/AML). Leuk Res. 2010;34:141-142.
Owen CJ, Toze CL, Koochin A, et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood. 2008;112:4639-4645.
Song W-J, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166-175.
Arepally G, Rebbeck TR, Song W, Gilliland G, Maris JM, Poncz M. Evidence for genetic homogeneity in a familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML). Blood. 1998;92(7):2600-2602.
Ho CY, Otterud B, Legare RD, et al. Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2. Blood. 1996;87(12):5218-5224.
Weiss HJ, Chervenick PA, Zalusky R, Factor A. A familial defect in platelet function associated with impaired release of adenosine diphosphate. N Engl J Med. 1969;281(23):1264-1270.
INTERNET
Deuitch N, Broadbridge E, Cunningham L, et al. RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies. 2021 Mar 4 [Updated 2024 Jan 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK568319/ Accessed Aug 22, 2024.
RUNX1-Familial Platelet Disorder (PDQ®)–Health Professional Version. National Cancer Institute. December 14, 2023. https://www.cancer.gov/publications/pdq/information-summaries/genetics/runx1-hp-pdq#_3755 Accessed Aug 22, 2024.
Atlas of Genetics and Cytogenetics in Oncology and Haematology. Familial Platelet Disorder with Predisposition to Acute Myelogenous Leukemia. Last Update September 2012.
https://atlasgeneticsoncology.org/Kprones/FamPlateletDisAMLID10079.html. Accessed Aug 22, 2024.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
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