Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML).

HELLER PAULA G; GLEMBOTSKY ANA C

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas online, Universidad de Poitiers, Francia

Año: 2013; p. 138 - 143

Familial platelet disorder with predisposition to acute myelogenous leukemia is a rare autosomal dominant disorder caused by heterozygous germline mutations in transcription factor RUNX1. Only fifteen pedigrees have been reported to date. The disease appears to have complete penetrance and affected individuals are born at the expected frequency for an autosomal dominant trait. There have been no reports of parental consanguinity among the pedigrees described so far, and males and females are equally affected. Together with CEBPA-associated leukemia and familial monosomy 7, FPD/AML represents one of the few identified genetic disorders underlying pure familial leukemia cases. Familial platelet disorder with predisposition to acute myelogenous leukemia is characterized by inherited thrombocytopenia, platelet function defect and a lifelong risk of myelodysplastic syndrome (MDS) and acute myelogenous leukaemia (AML). Thrombocytopenia is usually mild to moderate and is characterized by normal platelet size. Decreased expression of the thrombopoietin Mpl receptor has been found in these patients, providing a potential explanation for low platelet counts. Bleeding tends to be more severe than expected according to the degree of thrombocytopenia due to the presence of associated platelet dysfunction and results in a significant bleeding diathesis, which, although not severe, might be life-threatening after surgery or child-bearing. Platelet aggregation is abnormal in response to several platelet agonists although the mechanisms underlying this defect are not clear. Patients with FPD/AML are predisposed to myeloid malignancies, including AML and MDS. The rate of myeloid malignancies ranges between 20 to 65% and peaks at the fourth decade of life. Median age of leukemia onset is 37 years old, ranging from 6 to 75.  Germline RUNX1 mutations seem to be insufficient by themselves for leukemia development and acquisition of additional cooperating events are required. Several cytogenetic abnormalities have been identified in FPD/AML patients who develop myeloid neoplasms, including del(5q), -7/del(7q), +8, del(11q), 11q23 rearrangements, del (20q) and +21. On the other hand, no mutations have been found in the remaining RUNX1 allele in FPD/AML patients who developed leukemia.