NORD gratefully acknowledges Amy Trottier, MD, Department of Hematology, University of Calgary, and the RUNX1 Research Program for the preparation of this report.
Familial platelet disorder with associated myeloid malignancy (FPD/AML) is a very rare disorder caused by changes (mutations) in the RUNX1 gene. The RUNX1 gene was previously known as AML1 or CBFA2. FPD/AML is an inherited disorder, meaning that the mutated RUNX1 gene is passed down (inherited) from an affected parent such that patients with FPD/AML are born with the abnormal gene. FPD/AML is 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).
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 life-time; 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.
Symptoms of FPD/AML were first described in several members of a multigenerational family in 1969. Since that time additional families with similar symptoms and signs were found and in 1996 studies on a large family with FPD/AML isolated the problem to an abnormality on chromosome 21. More information on chromosomes is given in the “Causes” section of this report. In 1999 it was discovered that inherited (germline) alterations (mutations) in the RUNX1 gene, located on chromosome 21, was the cause of FPD/AML.
Common signs and symptoms of FPD/AML relate to the impact of inherited RUNX1 mutations on platelets and the increased likelihood of developing MDS and/or AML. Platelets are a type of blood cell that are made by specialized cells in the bone marrow (megakaryocytes). Platelets are an important component of our blood and their main function is to help to stop bleeding and form clots. This process is known as hemostasis.
Patients with FPD/AML may have a reduced number of platelets in their blood (thrombocytopenia) or may have platelets that do not function normally. Symptoms of low or dysfunctional platelets can include: easy or spontaneous bruising, frequent or severe nose bleeds (epistaxis), prolonged or excessive bleeding after procedures or surgery, heavy menstrual bleeding, bleeding from the gums, and small red spots on the skin (petechiae). Not every patient with FPD/AML is affected in the same way. The type and severity of symptoms can vary, even between patients in the same family. Importantly, some patients with FPD/AML may have only a minor decrease in platelet count with normal platelet function and have no symptoms of easy bruising or bleeding.
Mutations in the RUNX1 gene are also associated with a 35-40% life-time risk of developing MDS or AML. MDS is a type of blood disorder characterized by abnormal production and development of blood cells (red blood cells, white blood cells, and platelets) within the bone marrow, resulting in low blood counts. Common symptoms of MDS can include fatigue, weakness, easy bruising and bleeding, and frequent infections. (For more information on this disorder, choose “Myelodysplastic Syndromes” as your search term in the Rare Disease Database.)
AML is a type of blood and bone marrow cancer that progresses quickly and is fatal without treatment. Symptoms and signs of AML may include low blood counts, presence of immature cells (myeloblasts) circulating in the blood, fatigue, shortness of breath, weakness, abnormal bleeding or bruising, swollen sore gums, fevers, night sweats, weight loss, and frequent infections. (For more information on this disorder, choose “Acute Myeloid Leukemia” as your search term in the Rare Disease Database.)
FPD/AML is caused by inherited alterations (mutations) is 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). Mutations 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 (as discussed above). There are many different mutations in the RUNX1 gene that can cause FPD/AML and most families affected by this condition carry a unique mutation that is different from other families with this same disorder. The way in which mutations in RUNX1 cause a decrease in platelets and predispose patients to MDS and AML is not yet fully understood.
In FPD/AML, the mutation in RUNX1 is passed down (inherited) from the patient’s parents such that the patient is born with the gene mutation (a germline mutation). FPD/AML is an autosomal dominant disorder.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Spontaneous (de novo) genetic mutations are mutations that occur in the egg or sperm cell and are not inherited from the parents. De novo mutations in RUNX1 do not result in FPD/AML.
FPD/AML is a very rare disorder with an unknown incidence and prevalence. To date, more than 70 FPD/AML families (pedigrees) with inherited RUNX1 mutations have been identified. 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 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 there is no known racial predilection.
The diagnosis of FPD/AML is based on clinical suspicion following a thorough clinical history, physical examination, specialized blood tests, and confirmed through genetic testing detecting mutations in the RUNX1 gene. Persons newly diagnosed with AML or MDS, especially at a relatively young age, who have a history of low or abnormally functioning platelets or those with a family history of AML, MDS or other hematologic malignancies such as T-ALL or CMML may be referred for specialist evaluation and genetic testing.
Clinical Testing and Work-up
A detailed personal and family history will be taken. The doctor will be looking for clues for an underlying inherited disorder such as a personal history of easy bruising or bleeding, low platelets found on previous blood tests, or a family history of these same features as well as blood disorders or cancers.
Laboratory testing will include a complete blood count (CBC), peripheral blood smear, coagulation testing, and other routine blood tests. A CBC determines the number of red cells, white cells, and platelets in the blood. A peripheral blood smear involves looking at blood under a microscope to see if the blood cells appear irregular of if there any abnormal cells, like blast cells, circulating in the blood. Coagulation testing, such as the INR and PTT, provide information on the person’s ability to form blood clots and how long it takes to do so. Platelet function testing may also be performed. These tests are performed on blood samples taken from the patient’s vein (a process called venipuncture). Patients will be followed with a CBC at regular intervals to detect any changes.
A bone marrow aspirate and biopsy may be performed at the initial evaluation and/or at subsequent visits if there is any suspicion that the affected individual has developed AML, MDS, or another blood or bone marrow disorder. A bone marrow biopsy involves taking a sample of tissue (the bone marrow) and sending it to a laboratory specialist (pathologist) for further testing and examination under a microscope. The biopsy is usually, but not always, taken from the back part of the hip bone. During this procedure, the patient’s skin around the hip bone is cleaned and the skin and tissue covering the bone (periosteum) is then frozen with local anesthetic. A needle is inserted into the bone and samples of the liquid bone marrow (known as the bone marrow aspirate) as well as a small piece of the bone (the core biopsy) are removed.
To confirm a suspected diagnosis of FPD/AML, genetic testing can be performed on a tissue sample from the affected patient. Numerous tissues can be used for this purpose including the bone marrow, saliva samples, finger nails, hair, or skin. A skin biopsy is the preferred tissue source and can be obtained at the time of bone marrow biopsy by cutting a small piece of skin from around the bone marrow needle insertion point or by a punch biopsy. A punch biopsy is test where a small tube shaped portion of skin is removed using a pencil-like instrument with a sharp circular cutting edge.
If the diagnosis is confirmed and an inherited genetic mutation in RUNX1 is confirmed, the affected patient may be referred to a genetic counselor.
Diagnosis and management of FPD/AML may involve several medical professionals including: general practitioners, physicians who specialize in cancer (medical oncologists) or blood and bone marrow disorders (hematologists), genetics experts (medical geneticists or genetic councillors), nurses, pharmacists, and/or other health care professionals.
At present, there are no specific treatments available for patients with FPD/AML, however patients with this disorder who have significant 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 those 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 mutations prior to using them as a donor because they may carry the same inherited mutation. If the sibling has a RUNX1 mutation 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.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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.
Atlas of Genetics and Cytogenetics in Oncology and Haematology. Familial Platelet Disorder with Predisposition to Acute Myelogenous Leukemia. Last Update September 2012.
http://atlasgeneticsoncology.org/Kprones/FamPlateletDisAMLID10079.html. Accessed Sept. 5, 2018.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100