title: Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.
abstract: Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterized 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. Germ- line 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 hematopoietic stem cell transplantation 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 posttransplantation 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, before consideration of sibling hematopoietic stem cell transplantation.
authors: Centre for Medical Oncology, Barts and the London School of Medicine & Dentistry, London, United Kingdom. cowen@bccancer.bc.ca
authors: Carolyn J
authors: CJ
authors: Owen
authors: Cynthia L
authors: CL
authors: Toze
authors: Anna
authors: A
authors: Koochin
authors: Donna L
authors: DL
authors: Forrest
authors: Clayton A
authors: CA
authors: Smith
authors: Jane M
authors: JM
authors: Stevens
authors: Shannon C
authors: SC
authors: Jackson
authors: Man-Chiu
authors: MC
authors: Poon
authors: Gary D
authors: GD
authors: Sinclair
authors: Brian
authors: B
authors: Leber
authors: Peter R E
authors: PR
authors: Johnson
authors: Anthony
authors: A
authors: Macheta
authors: John A L
authors: JA
authors: Yin
authors: Michael J
authors: MJ
authors: Barnett
authors: T Andrew
authors: TA
authors: Lister
authors: Jude
authors: J
authors: Fitzgibbon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001791:Blood Platelet Disorders / Q000150:complications / Q000235:genetics*; D002648:Child; D000075202:Contraindications; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005190:Family; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human