What is RUNX1 FPD/AML?

RUNX1 FPD/AML is a hereditary blood disorder which predisposes an individual to acquiring leukemia in his or her lifetime.  Individuals with FPD/AML have only one of two functional RUNX1 genes, as the second is mutated.

What is RUNX1?

RUNX1 is a gene located on chromosome 21 in humans. It encodes a protein that is also called RUNX1.  RUNX1 is a transcription factor, meaning it helps to regulate the expression of other genes. RUNX1 is particularly important for the formation and function of blood cells.

What Is A Hereditary/Genetic Disorder?

A gene is the basic physical and functional unit of heredity. Genes are made up of DNA which spells out specific instructions, like a cookbook recipe, for making proteins in the cell. Proteins are the building blocks for everything in our body, but sometimes genes get damaged in ways that cause problems from birth. As cells divide and multiply, they have to make copies of our DNA, and, over time, mistakes can happen and accumulate. Most genetic disorders are due to spontaneous mutations that first happened long ago in a particular individual which are then passed down to the subsequent generations.

How do mutations in RUNX1 cause the FPD/AML disorder?

A RUNX1 mutation is a permanent alteration in the DNA sequence that makes up the RUNX1 gene, such that the sequence differs from normal. In those with FPD/AML, one copy of the RUNX1 gene is mutated, and the result is overall reduced levels of normal RUNX1 protein. A normal amount of RUNX1 protein is required for the proper development of megakaryoctyes, and these cells are what produce platelets (the part of our blood responsible for clotting). Hence, individuals with RUNX1 FPD/AML typically have low platelet counts (thrombocytopenia) along with dysfunctional platelets. See below for how RUNX1 FPD/AML can progress to leukemia.

What is thrombocytopenia?

Thrombocytopenia is a low platelet count.  Each laboratory has its own normal range for platelet counts, but a common lower limit of normal is often stated at 150,000/µL. A common upper limit for a normal platelet count is often stated at 450,000/µL.  Looking at the platelet count alone in a person with FPD/AML can be misleading because some people/families have platelet counts within the normal range.  This probably contributes to the under-diagnosis of FPD/AML.

In general, the lower the platelet count, the greater the bleeding risk. Bleeding due to thrombocytopenia tends to involve excessive or large skin bruises termed “purpura" disproportionate to any trauma, and also “petechiae”, which are pinpoint burst blood vessels usually in dependent parts of the body such as the ankles or areas of mild trauma. Nosebleeds, gum oozing, heavy periods or hemorrhage at childbirth for women, and bleeding with surgery may all be seen with thrombocytopenia. Intracranial bleeds into the brain are the most serious bleeding issues and may occur after little or no head trauma.

Can RUNX1 mutations be corrected and re-transplanted into human patients?

Not yet. However scientists around the world are trying to find ways to correct mutations in patients’ blood cells and generate corrected stem cells that can give rise to a blood system that lasts the lifetime of the individual. Right now, scientists can correct stem cells in the laboratory, but they can’t yet make stem cells that are long-lasting.

Can I live a normal life with RUNX1 FPD/AML?

For the most part, yes. Individuals with RUNX1 FPD/AML typically present as having low platelets (thrombocytopenia), and the platelets they have are functionally impaired, causing bleeding problems such as nose bleeds, excessive bleeding during minor surgery, and easy bruising. The severity of one’s platelet count determines the quality of one’s life.

While the bleeding manifestations in FPD/AML do not require daily attention, being followed by a hematologist with expertise in platelet disorders is important for several reasons including the need to receive proper education and to optimize care. It is typically recommended to avoid aspirin and non-steroidal analgesics, to maintain optimal dental and gum care, and to know how to manage nosebleeds and the warning signs of an intracranial bleed. Management of menorrhagia is usually done in combination with a gynecologist. It is highly important that both your surgeon and hematologist are in contact for correct surgical management.

In terms of progression to leukemia, RUNX1 FPD/AML carries a 50 percent lifetime risk of leukemia through the acquisition of additional mutations in other genes.*According to a 2014 review of 11 FPD/AML papers, "Distinct FPD/AML families have varying risks of progression to myeloid malignancy (range, 11%-100%; median, 44%).” Godley, Lucy A., “Inherited Predisposition to Acute Myeloid Leukemia”, http://www.slaop.org/pdf/291LeucemiaInheritedPredispositiontoAcuteMyeloi... Approximately 38.5 percent of men and women in America will be diagnosed with cancer of any site at some point during their lifetime, based on 2012-2014 data provided by cancer.gov. Having RUNX1 FPD/AML increases one’s odds, but this should not be to the detriment of one’s quality of life. Additionally, some family natural histories have their FPD/AML progress to leukemia at later stages of life while some earlier. Much research remains to be done in this realm, and we hope you consider participating in our Patient Registry (coming 2018).

How can I get screened to know if I have RUNX1 FPD/AML?

Blood tests are used to determine whether you have the disorder. Your hematologist/oncologist will ask you about symptoms and family history and then can extract either blood or bone marrow to have it sequenced to determine whether you have the RUNX1 gene mutation. Typically, those with RUNX1 FPD/AML present as having low platelets (thrombocytopenia), and the platelets they have are functionally impaired. One may experience more bruising and bleeding than the norm, slower blood clotting, and females can suffer from menorrhagia.

Individuals with bleeding problems or a family history of thrombocytopenia, leukemia, ITP (immune thrombocytopenic purpura), or other cancers are advised to ask their physicians about genetic testing for inherited leukemia predisposition genes.

Note that there have been some patients with RUNX1 FPD/AML who have a platelet count as high as 150,000/µ3. While the platelet count can be near normal in few cases, the platelets are still often functionally defective, it appears.

Will my health insurance cover the costs of genetic testing?

There is a wide range of coverage for genetic testing, so it is important to check with your insurance carrier. A genetic counselor or physician can request pre-authorization before testing if individuals are concerned about cost, but it is important to know that pre-authorization decisions are not binding. The costs of the testing depend on the type of genetic testing being ordered.

Who gets RUNX1 FPD/AML?

RUNX1 FPD/AML is an autosomal dominant disorder. ‘Autosomal’ because the RUNX1 gene is located on human chromosome 21, which is not one of our sex chromosomes, X/Y.   ‘Dominant’ because it only takes mutation of one of your two copies of RUNX1 to give you the condition.  Additionally, a person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene with each pregnancy. The chance that a child will not inherit the mutated gene is also 50 percent. Only one parent needs to have the genetic mutation to pass it on to their children, and if a sibling has the disease, there is no greater or lesser likelihood of the other siblings having it also. Children who do not inherit the abnormal gene will not develop nor pass on the disease.

People of any race or ethnicity can get RUNX1 FPD/AML. Although considered a rare disorder, the frequency of FPD/AML has been historically underestimated. Incidence has increased in recent years with awareness and access to genetic testing.


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