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A novel acquired inv(2)(p23.3q24.3) with concurrent submicroscopic deletions at 2p23.3, 2p22.1, 2q24.3 and 1p13.2 in a patient with chronic thrombocytopenia and anemia

2015-02-01 15:50:01

MOLECULAR CYTOGENETICS; 1 February 2015: DOI:10.1186/s13039-015-0113-z


Eigil Kjeldsen



Abstract



Background



Thrombocytopenia can result from a wide range of conditions and may be determined by multiple mechanisms. It can be due to a reduced platelet production or an increased destruction of platelets. Increased destruction is seen in conditions such as disseminated intravascular coagulation (DIC) and thrombotic microangiopathies, whereas decreased production is seen in bone marrow (BM) failure syndromes such as aplastic anemia, myelodysplastic syndromes, and chemotherapy-induced thrombocytopenia. In BM failure syndromes thrombocytopenia is often accompanied by anemia and/or leucopenia. Recognition of the cause of thrombocytopenia is often crucial for correct management of patients.



Case Presentation



Here, we report on a 71 year-old male caucasian with thrombocytopenia since six years, and a recent development of anemia. At the time of progression with anemia a bone marrow sampling was done to examine for a possible causative myeloid malignancy. The morphological examination was normal whereas immunophenotyping by flowcytometry could not exclude myelodysplasia. Cytogenetic analysis by G-banding revealed a pericentric inversion of chromosome 2 in 23 out of 25 analyzed metaphases. The inversion was further characterized by molecular cytogenetics and high-resolution oligo-based array-CGH analysis. Together the analyses demonstrated a 141.8 Mb pericentric inversion, inv(2)(p23.3q24.3), and concurrent submicroscopic deletions in 2p23.3, 2p22.1, 2q24.3 and 1p13.2 between 0.6-1.9 Mb in size. Locus-specific FISH analyses confirmed all deletions and the pericentric inversion of chromosome 2. The chromosomal abnormalities were present in 87% of the bone marrow cells whereas analysis of a skin biopsy revealed a normal male karyotype as well as a normal array-CGH result. These findings demonstrate that the identified abnormalities were acquired.



Conclusion


To the best of our knowledge, this is the first report of chronic thrombocytopenia and anemia associated with acquired inv(2)(p23.3q24.3) as a sole cytogenetic abnormality together with concurrent submicroscopic deletions at 2p23.3, 2p22.1, 2q24.3 and 1p13.2.



Background


Idiopathic thrombocytopenic purpura (ITP) is a common hematologic disorder that affects patients of all ages and with equal sex ratio. Primary ITP is defined as isolated thrombocytopenia (platelet count < 100 x 109/L) in absence of other causes or disorders that may be associated with thrombocytopenia. Chronic thrombocytopenia is defined as disease of more than 12 months duration. Acquired thrombocytopenia may also be part of pancytopenia in myelodysplastic syndromes (MDS) or in acute myeloid leukemia (AML) when either anemia and/or leucopenia are present



Recognition of the cause of thrombocytopenia is important for proper treatment of the patients. Cytogenetic evaluation is a prerequisite in diagnostic work-up of myeloid malignancies to provide valuable prognostic information and to determine treatment strategies. Several recurrent cytogenetic abnormalities have been identified in myeloid malignancies and these have conveyed into risk stratification groups.



In cases with isolated thrombocytopenia cytogenetic evaluation is uncommon and only few cytogenetic abnormalities have been associated with isolated thrombocytopenia. Thrombocytopenia-absent radius syndrome is a rare autosomal recessive disorder that has been associated with either RBM8A gene mutation or a 1.35 Mb microdeletion in 1q21.1. In cases where isolated thrombocytopenia evolves with additional cytopenias or in cases where these are present upfront it is suggestive of possible underlying MDS or AML. In these cases examination of the bone marrow by morphology, flow cytometry and cytogenetic analyses are usually performed.



Here is reported the molecular cytogenetic and array-based CGH characterization of a patient with chronic thrombocytopenia and anemia without dysplastic signs or increased blasts in the bone marrow. We identified a novel acquired pericentric inversion of chromosome 2, inv(2)(p23.3q24.3), as a sole cytogenetic abnormality together with four additional concurrent submicroscopic deletions in 2p23.3, 2p22.1, and 2q24.3 and 1p13.2. These chromosomal abnormalities have not been reported previously.



Case Presentation : Clinical Report


A 71-year old male was referred to our Hematological Department in January 2013 suspected for MDS. He had an acute myocardial infarction (AMI) in 1999 and recovered from this without complications except for dyspnea. He has been on anti-thrombotic medication with Warfarin and Aspirin since. At the time of referral to our department he had had thrombocytopenia since 2008 with values between 87 – 124 x 109/L and developed additionally moderate anemia (hemoglobin 7.4 mM) in December 2012. His white blood cell counts were in the years 2008 – 2013 within normal range whereas he had a moderate increase in LDH with values between 264 – 398 U/L. Physical examination revealed areas with bruising of his skin. He has epistaxis once every second month. He had been smoking until approximately 6 months prior to referral with a calculated 10 pack years.



As part of the diagnostic work-up in January 2013 a bone marrow examination was performed including morphology and cytogenetic analyses. The morphological examination was normal whereas the cytogenetics analysis revealed a pericentric inversion of chromosome 2 in 23 out of 25 analyzed metaphases. Watchful waiting was decided with additional cytogenetic work-up (se below for further description). Eighteen month after referral a follow-up examination of his bone marrow cells included morphology, flow cytometry and cytogenetic analyses. Morphology examination was still without dysplastic signs or increased blasts whereas flow cytometry could not exclude myelodysplasia. Biochemistry at one-year follow-up was without progression and showed continued thrombocytopenia (platelets, 92 x 109/L) with moderate anemia (hemoglobin, 7.2 mM). He is continuously well and without development in symptoms, and visits our hospital for regular follow-ups.



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Key Words


Thrombocytopenia | Anemia | Chromosome 2 | Inversion | Microdeletion | aCGH