Abstract
BackgroundChromosome changes in the bone marrow (BM) of patients with persistent cytopenia are often considered diagnostic for a myelodysplastic syndrome (MDS). Comprehensive cytogenetic evaluations may give evidence of the real pathogenetic role of these changes in cases with cytopenia without morphological signs of MDS.ResultsChromosome anomalies were found in the BM of three patients, without any morphological evidence of MDS: 1) an acquired complex rearrangement of chromosome 21 in a boy with severe aplastic anaemia (SAA); the rearrangement caused the loss of exons 2–8 of the RUNX1 gene with subsequent hypoexpression. 2) a constitutional complex rearrangement of chromosome 21 in a girl with congenital thrombocytopenia; the rearrangement led to RUNX1 disruption and hypoexpression. 3) an acquired paracentric inversion of chromosome 1, in which two regions at the breakpoints were shown to be lost, in a boy with aplastic anaemia; the MPL gene, localized in chromosome 1 short arms was not mutated neither disrupted, but its expression was severely reduced: we postulate that the aplastic anaemia was due to position effects acting both in cis and in trans, and causing Congenital Amegakaryocytic Thrombocytopenia (CAMT).ConclusionsA clonal anomaly in BM does not imply per se a diagnosis of MDS: a subgroup of BM hypoplastic disorders is directly due to chromosome structural anomalies with effects on specific genes, as was the case of RUNX1 and MPL in the patients here reported with diagnosis of SAA, thrombocytopenia, and CAMT. The anomaly may be either acquired or constitutional, and it may act by deletion/disruption of the gene, or by position effects. Full cytogenetic investigations, including a-CGH, should always be part of the diagnostic evaluation of patients with BM aplasia/hypoplasia and peripheral cytopenias.
Highlights
Chromosome changes in the bone marrow (BM) of patients with persistent cytopenia are often considered diagnostic for a myelodysplastic syndrome (MDS)
In the years 2000–2011 we performed cytogenetic investigations, as part of routine work, in 87 pediatric patients with persistent cytopenia, either uni, bi- or trilinear, during their diagnostic evaluation. In this heterogeneous cohort we found monosomy 7 and trisomy 8 in two patients each, all eventually diagnosed as MDS; increased chromosome breakage was observed in three cases diagnosed as Fanconi anaemia (FA); an isochromosome for the long arms of chromosome 7 was present in one patient with previously undiagnosed Shwachman-Diamond Syndrome; trisomy 8 was found in one patient in whom MPL gene mutations demonstrated a congenital amegacaryotic thrombocytopenia (CAMT, OMIM # 604998) [2]; a translocation t(8;17)(p21;q25) was present in a patient with features of Blackfan-Diamond Anaemia
Patient 1 The chromosome analyses on BM revealed a clonal structural anomaly of chromosome 21, der(21), present since 2004, a few months after the disease onset, up to June 2009, whereas analyses performed at two different dates in 2006 on peripheral blood (PB) phytohaemagglutinin (PHA)-stimulated cultures showed a normal karyotype in 100 mitoses scored
Summary
Chromosome changes in the bone marrow (BM) of patients with persistent cytopenia are often considered diagnostic for a myelodysplastic syndrome (MDS). In the years 2000–2011 we performed cytogenetic investigations, as part of routine work, in 87 pediatric patients with persistent cytopenia, either uni-, bi- or trilinear, during their diagnostic evaluation In this heterogeneous cohort we found monosomy 7 and trisomy 8 in two patients each, all eventually diagnosed as MDS; increased chromosome breakage was observed in three cases diagnosed as Fanconi anaemia (FA); an isochromosome for the long arms of chromosome 7 was present in one patient with previously undiagnosed Shwachman-Diamond Syndrome; trisomy 8 was found in one patient in whom MPL gene mutations demonstrated a congenital amegacaryotic thrombocytopenia (CAMT, OMIM # 604998) [2]; a translocation t(8;17)(p21;q25) was present in a patient with features of Blackfan-Diamond Anaemia. A paracentric inversion of chromosome 1 was present, and we postulate that it led to aplastic anaemia through position effects on the MPL gene, with severely reduced expression; this interpretation turned the diagnosis to CAMT
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