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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4639-4645.
Prepublished online as a Blood First Edition Paper on August 21, 2008; DOI 10.1182/blood-2008-05-156745.
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Submitted May 20, 2008
Accepted August 8, 2008
Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy (FPD/AML)
Carolyn J Owen*, Cynthia L Toze, Anna Koochin, Donna L. Forrest, Clayton A Smith, Jane M Stevens, Shannon C Jackson, Man-Chiu Poon, Gary D Sinclair, Brian Leber, Peter R.E. Johnson, Anthony Macheta, John A.L. Yin, Michael J Barnett, T Andrew Lister, and Jude Fitzgibbon
Medical Oncology, Barts and the London School of Medicine, London, United Kingdom
Division of Hematology, Leukemia/BMT Program of BC, Vancouver, Canada
Division of Hematology and Hematologic Malignancies, University of Calgary, Calgary, Canada
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada
Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, Canada
Department of Haematology, Western General Hospital, Edinburgh, United Kingdom
Department of Haematology, University of Morecambe Bay NHS Trust, Furness, United Kingdom
University Department of Haematology, Manchester Royal Infirmary, Manchester, United Kingdom
* Corresponding author; email: cowen{at}bccancer.bc.ca.
Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterised by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first degree relative with MDS/AML for inherited mutations in RUNX1. Germline RUNX1 mutations were identified in 5 pedigrees with a 3:2 predominance of N-terminal mutations. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included haematopoietic stem cell transplantation (HSCT) from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment and post-transplantation lymphoproliferative disorder. Given the small size of modern families and the clinical heterogeneity of this syndrome, the diagnosis of FPD/AML could be easily overlooked and may be more prevalent than previously recognized. Therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, prior to consideration of sibling HSCT.
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