Platelet Disorder, Familial, With Associated Myeloid Malignancy

A number sign (#) is used with this entry because of evidence that familial platelet disorder with associated myeloid malignancy (FPDMM) is caused by heterozygous mutation in the hematopoietic transcription factor CBFA2 (RUNX1; 151385) on chromosome 21q22.

Clinical Features

Dowton et al. (1985) described a large pedigree with an autosomal dominant familial 'aspirin-like' platelet disorder associated with the development of acute myelogenous leukemia (AML).

Arepally et al. (1998) reported a family of mixed Czechoslovakian and Hungarian background with a phenotype similar to the family of Dowton et al. (1985). The proband presented at the age of 4 years for hypospadias repair. He had easy bruising since infancy and was found preoperatively to have a platelet count of 106,000/microliter. The mother, maternal aunt, and maternal grandmother had low platelet counts and a bleeding diathesis. In addition to thrombocytopenia, both the index patient and his brother had hypospadias and umbilical hernia. At 41 years of age, the proband's mother developed progressive anemia and neutropenia and was shown to have refractory anemia. Within 6 months of diagnosis of myelodysplasia, increased marrow blast counts above 30% were noted. Cytogenetics yielded normal results, as did fluorescence in situ hybridization studies for monosomy 5 and 7. Immunohistochemical typing of her blasts confirmed acute myelogenous leukemia.

Beri-Dexheimer et al. (2008) reported a boy who presented at age 2 years with purpura without history of easy bruising or bleeding. Although platelet morphology was normal, he had thrombocytopenia, and the platelets showed impaired aggregation in response to ADP. A bone marrow aspirate showed a hypercellular bone marrow with blasts (20%) and myelodysplastic features. Blasts phenotype was immature with myeloid markers leading to a diagnosis of AML. He underwent successful bone marrow transplantation. His mother, who had no history of bleeding, was found to have mild isolated thrombocytopenia and similarly abnormal platelet behavior. Molecular analysis identified a heterozygous deletion in the RUNX1 gene (151385.0009) in the patient and his mother.

Preudhomme et al. (2009) reported 16 individuals with familial platelet disorder from 4 unrelated French families associated with heterozygous mutation in or deletion of the RUNX1 gene (see, e.g., 151385.0010). Among these patients, 7 developed AML, 1 had a T-acute lymphoblastic leukemia, 1 had T-ALL followed by AML, and 1 died of an uncharacterized leukemia. Of the 8 with AML, age at diagnosis of AML ranged from 12 to 60 years, and 6 were found to have a somatic RUNX1 mutation: 4 had acquired point mutations and 2 had acquired trisomy 21. The findings indicated that a second genetic event involving RUNX1 is often associated with progression to acute leukemia in patients with familial platelet disorder. In addition, heterozygous mutations in the RUNX1 gene may also predispose to the development of lymphoblastic leukemia.

Mapping

In the large family described by Dowton et al. (1985), Ho et al. (1996) found linkage of the platelet disorder to markers D21S263, D21S216, IFNAR (107450), and D21S65 on chromosome 21q, with lod scores of 6.19, 4.89, 9.40, and 10.48, respectively (theta = 0.001). They proposed a familial platelet disorder critical region of 15.2 cM in addition to approximate placement for markers D21S211 and UT7582/D21S1413. This critical region contains 5 candidate genes, including AML1 (151385), IFNAR, CRF2-4 (123889), GART (138440), and SON (182465). See also 176630.

By linkage analysis of a family with this disorder, Arepally et al. (1998) found evidence for linkage to chromosome 21 (maximum lod score of 1.682 at D21S65). Multipoint analyses placed the putative disease locus between D21S263 and D21S211. Maximum lod scores greater than 3 were obtained at each map interval. No evidence for allele sharing between this kindred and the French Canadian pedigree reported by Ho et al. (1996) was found.

Genetic Heterogeneity

Minelli et al. (2004) stated that 12 families with familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML) had previously been reported. They described an Italian family with 3 members affected with FPD/AML, 2 sibs and their father, who developed myelodysplastic syndromes, which in one subsequently evolved into AML. Direct sequencing and polymorphism haplotype analysis of the region of chromosome 21 where the RUNX1 gene maps demonstrated that FPD/AML in this family was not caused by mutation in the RUNX1 gene, thus providing evidence for the genetic heterogeneity of the disorder. Cytogenetic studies showed monosomy 7 in the marrow of all 3 affected subjects, as well as an independent clone with trisomy 8 in the father.

Molecular Genetics

By mutation analysis of candidate genes in the region where this familial platelet disorder maps, Song et al. (1999) found a heterozygous mutation in the hematopoietic transcription factor CBFA2 (see, e.g., 151385.0001; 151385.0002) in affected members of 6 families. Analysis of bone marrow or peripheral blood cells from affected individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. The authors suggested a model for this familial platelet disorder in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to an acquisition of additional mutations that cause leukemia.

In affected members of 3 unrelated families with the autosomal dominant familial platelet disorder characterized by thrombocytopenia and a propensity to develop AML, Michaud et al. (2002) identified 3 heterozygous mutations in the RUNX1 gene (151385.0003-151385.0005).