Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q

Abstract

Several lines of evidence support the presence of dosage-sensitive genes on chromosome 21 that regulate leukemogenesis and hematopoiesis. We report a detailed clinical and molecular characterization of 3 patients with chronic thrombocytopenia caused by distinct constitutional microdeletions involving chromosomal region 21q22.12. The patients exhibited growth restriction, dysmorphic features, and developmental delays.One patient developed acute myelogenous leukemia (AML) at 6 years of age. All 3 deletions included the RUNX1, CLIC6, DSCR, and KCNE1 genes. Our data provide additional support for the role of RUNX1 haploinsufficiency in megakaryopoiesis and predisposition to AML. The leukemic clone had trisomy 21 resulting from duplication of chromosome 21 containing the RUNX1 deletion. This shows that genes other than RUNX1 must also play a role in AML associated with trisomy 21. We recommend that children with syndromic thrombocytopenia have clinical array-comparative genomic hybridization analysis and appropriate cytogenetic studies to facilitate our ability to provide a definitive diagnosis. (Blood. 2008; 112:1042-1047)

Familial myelodysplastic syndromes: a review of the literature

“…The clinical features of reported cases where descriptions of hematologic findings were available are summarized in Table 2. [28][29][30][31][32][33][34][35][36] All but one case 32 reported thrombocytopenia, with qualitative platelet defects described in 2 cases. 30,36 MDS/AML developed in 3 cases, with a median age of onset of six years (range 5-8 years).…”

Myeloid neoplasms with germ line RUNX1 mutation

“…In some FPD/ AML patients who lack CDC25C mutation, Sakurai et al identified TET2 mutation or abnormal chromosome 21 (trisomy 21) with chromosomal deletion encompassing RUNX1 locus [27]. Since both genetic events are involved in clonal expansion of HSCs and progenitors (HSPCs) [38][39][40][41], TET2 mutation or trisomy 21 could cooperate with RUNX1 haploinsufficiency to generate pre-leukemic clones. Those patients further acquired additional mutations, such as mutations in RB1, ZRSR2, and BCOR, and eventually developed overt MDS [27].…”

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

“…Rare cases reporting intragenic deletion of RUNX1 gene or duplication of the chromosome 21 carrying the RUNX1-deleted or mutated allele may have similar phenotype. [29][30][31] A recent study indicated that familial platelet disorder should be suspected in AML cases with a RUNX1 biallelic mutation or with a single RUNX1 mutation with a variant allele frequency more than 50%, which could indicate trisomy 21 with a duplication of the mutated chromosome or loss of heterozygosity.…”