A FAMILY INHERITING DIFFERENT SUBTYPES OF ACUTE MYELOGENOUS LEUKEMIA

Rare Inherited cancer syndromes have proven invaluable for the identif ication of genes involved in the more frequent corresponding noninheri ted cases. We report on a family with an adult onset, incompletely pen etrant, autosomal dominant syndrome of myelodysplasia and acute myelog enous leukemia, affecting at least eight, and probably ten, individual s from three generations. The patients have developed leukemias differ ing in morphologic subtype, tumor cytogenetics, and abruptness of pres entation. Some have presented with acute onset and others with protrac ted myelodysplasia. This family does not have an unusual incidence of other malignancies; however, one person at 50% risk of inheriting this gene developed atypical mycobacterium infection in the absence of leu kemia, but also without appreciable risk factors for acquired deficien cies in cellular immunity. Features common to affected family members, including the individual with mycobacterium infection, are the early presence in the bone marrow of red cell and platelet maturation defect s, A search for mutations in diseased marrows fails to detect abnormal ities of p53 or N-ras. Two of the affected family members, third degre e relatives, have co-inherited a constitutional chromosomal banding va riation of 9p21-22, potentially suggesting linkage to this locus, The variable penetrance and expressivity of this syndrome support a multis tep model of leukemia evolution, in which the gene defined by this fam ily's syndrome is the signal step. (C) 1996 Wiley-Liss, Inc.