RUNX1...I hope someone knows abourt this. Do you?

Brand new to the group...first post, and glad to find you!

My husband (and one of his brothers) had "the tendency to bleed" as children. He was told he grew out of it, but his brother never did. His platelet count was within but at the low end of normal for many yr (he is 41). On a recent preoperative appt for an unrelated surgery, his platelet count was in the 50K's. We insisted on seeing a hematologist to get to the source of the issue. After many tests, he was told he has ITP-immune thrombocytopenia purpura. They did another test that was a genetic test to determine if he has the gene mutation that correlates higher incidence of familial thrombocytopenia developing leukemia. Well, the test was positive.

I know that the positive test result doesn't mean he will get leukemia, but that there is a higher incidence.

What can you tell me about this RUNX1?

They said we need to have our 10 month old tested. UGH!

other pertinent info: His brother, whom has always been much more symptomatic, has a 12 yr old daughter that is also highly symptomatic. She required transfusion and emergent care when she began her menstrual cycle. They didn't test her, evidently, for diagnosis, only administering hormone therapy to minimize bleeding.

I have read that the RUNX1 mutation has only been identified in approximately 20 families as of a few years ago.

If you have any information, please, please share!!
Thank you!
I look forward to learning from your experiences!

GLW:

Hello there - sorry you had to find us. The disorder that you are talking about is different than ITP which is what most of us have here. It's pretty rare for someone to actually have a diagnosed familial platelet disorder on the Forum. I don't see it very often and I've been here for 14 years. I don't know whether doctors don't look into it often enough or it truly is that rare, but it is a different scenario than what we are dealing with. I couldn't even tell you if the treatments are the same.

I did find this which may be helpful if you can get psat the medicalese. It is from 2004, so there may be updated info around. Blood Journal is a very credible site though.

"Familial platelet disorder with associated myeloid malignancy (OMIM: 601399 [OMIM] FPDMM). In 1996, a large kindred was reported with autosomal dominant thrombocytopenia and a striking predisposition for hematologic malignancy.22 In this family, the degree of thrombocytopenia was mild to moderate, and platelets had normal size and appearance. However, bleeding times were prolonged and an aspirin-like defect in aggregation studies was observed.22 Linkage analysis narrowed the affected gene to an interval on human chromosome 21q22.1-22.2.22

Etiology. The abnormal gene has been identified as AML1, also known as CBFA2 and RUNX1. FPDMM has now been associated with either deletion of a single allele (eg, haploinsufficiency) or point mutations of AML1 that abrogate DNA binding of the runt domain.23,24 Evidence suggests that mutated forms of AML-1 that can heterodimerize with PEBP2{beta}/CBF{beta} in a dominant-negative manner have a higher rate of hematologic malignancy than gene deletion.24 Confirming its role in hematopoiesis, disruption of the cbfa2 gene in mice caused failure of definitive hematopoiesis and lethal hemorrhage during embryonic days 11.5 to 12.5.25 Interestingly, hemizygous deletion of one cbfa2 allele resulted in lower erythroid and myeloid colonies (CFU-MK and platelet counts were not reported).25 Suppression of runx1 in zebrafish results in failure of hematopoiesis as well as angiogenesis, suggesting a critical role for the gene in the hemangioblast.26 It is not clear why, in humans, the heterozygous loss of AML1 function as a transcription factor and tumor suppressor during hematopoiesis should result in a phenotype that is primarily thrombocytopenia.

Special circumstances: related stem cell transplantation in FPDMM. Because of the high incidence of myeloid leukemia at a relatively young age (< 60 years), it is likely that many affected individuals will eventually undergo hematopoietic stem cell transplantation. Unless the clinician is aware of the potential for FPDMM, mild thrombocytopenia in an HLA-matched sibling might be overlooked. There has already been at least one reported case of a transplant from a sibling in which both the donor and recipient subsequently developed donor-derived leukemia. If a mutation in AML1 has been identified in a patient with FDP/AML, then potential sibling donors should be screened for this mutation, even if the platelet count is normal."

bloodjournal.hematologylibrary.org/content/103/2/390.full.html

Thanks for the reply.

What is odd... They did testing. Sent to Duke Univ. for Immune Thrombocytopenia Purpura. It was Positive! Then reports came back from (prevention genetics I think) showing a + Runx1 gene also.

Evidentally he has both...or the ITP is a form of the familial thrombocytopenia?!

I'll keep searching.
Thanks again

The word thrombocytopenia means low platelets, and can be caused by a number of things. Technically, ITP is also low platelets, but is caused by an autoimmune dysfunction (not enough production and too much destruction). There really isn't a specific test for ITP, so I don't know what would have come back positive. There are anti-platelet antibody tests, but they are not reliable and don't mean much in the scheme of things. Some people with ITP have them and some do not. My guess is that they did those antibody tests and one or more did show the antibodies. The fact that he has Runx1 may or may not make a difference if he has to treat. That is the part that I can't help you with. ITP is usually a diagnosis of exclusion, so there really isn't anything that positively identifies it.

My sister and I have both had ITP. I knew what it was long before I was diagnosed (1998) because my sister had it in 1980. I have never thought it was rare because I have actually known of several people in my life who have had it. It seems pretty common to me. I think you have a very astute doctor there who went above and beyond and actually tested your family members for familial ITP instead of just assuming it is Immune TP. He could have both; I don't know. With ITP, platelets are usually larger than normal because we tend to have new (reticulated) platelets. The article above says that platelets are normal-sized with Runx1. I honestly don't know enough about it to tell you what is going on.

Right! They did a anti-platelet antibody test through Duke Univ. Which is what was positive, hence ITP. He was also familiar with the term ITP from his childhood in the late 60's and early 70's. However, the I was for idiopathic...as I'm sure you're aware.

What a cobweb of info to sort through!

Thanks for the info again. I'm glad you commented about his doc. He does seem to be very thorough. I had been pleased with him so far, but it made me really eval things and I am really pleased with his diagnostics and treatment so far.

I'm sure I'll have more questions. I am still hopeful you all here can share your knowledge to help.
thanks again!
G

Hi G, the I in ITP used to be for Idiopathic as they didn't know the cause. Now they know it's an autoimmune disorder they changed the I to mean Immune. But as Sandi says there is a Familial Thrombocytopenia which is not ITP although lots of people are still wrongly diagnosed. Your family are lucky to have got the proper diagnosis so quickly.

I'm late to the party but thought I'd throw my two cents in. This article states that those with familial ITP often don't respond to typical ITP treatments. It's really interesting to read all this about a disease I have that I really don't understand

asheducationbook.hematologylibrary.org/cgi/content/full/2004/1/390