Background and objective: Pediatric myelodysplastic syndrome (pMDS) is a group of rare clonal neoplasms with a difficult diagnosis and risk of progression to acute myeloid leukemia (AML). The early stratification in risk groups is essential to choosing the treatment and indication for allogeneic hematopoietic stem cell transplantation (HSCT). According to the Revised International Prognostic Scoring System, cytogenetic analysis has demonstrated an essential role in diagnosis and prognosis. In pMDS, abnormal karyotypes are present in 30-50% of the cases. Monosomy 7 is the most common chromosomal alteration associated with poor prognosis. However, the rarity of specific cytogenetic alterations makes its prognosis uncertain. Thus, this study aimed to describe uncommon cytogenetic alterations in a cohort of 200 pMDS patients and their association with evolution to AML. Methods: The cytogenetic analysis was performed in 200 pMDS patients by G-banding and fluorescence in situ hybridization between 2000 to 2022. Results: Rare chromosome alterations were observed in 7.5% (15/200) of the cases. These chromosome alterations were divided into four cytogenetic groups: hyperdiploidy, biclonal chromosomal alterations, translocations, and uncommon deletions, which represented 33.3%, 33.3%, 20%, and 13.3%, respectively. Most of these patients (10/15) were classified with advanced MDS (MDS-EB and MDS/AML) and the initial subtype was present in five patients (RCC). The leukemic evolution was observed in 66.66% (10/15) of the patients. Most patients had poor clinical outcomes and they were indicated for HSCT.  Conclusion: The study of uncommon cytogenetic alterations in pMDS is important to improve the prognosis and guide early indication of HSCT. Keywords: Pediatric MDS; Leukemic evolution; rare chromosomal altwerations; HSCT, Children

Background/Objectives: Pediatric myelodysplastic syndrome (pMDS) is a rare, heterogeneous, clonal hematopoietic stem cell disease with a risk of evolution to acute myeloid leukemia (AML). Clonal cytogenetic abnormalities are present in 30–60% of pMDS. However, unlike in adults, the prognostic significance of chromosomal alterations, particularly their role in predicting evolution to AML, remains limited in pMDS. To acknowledge this gap, we studied the cytogenetic abnormalities in pMDS and analyzed their associations with subtypes and evolution to AML. Furthermore, in the Discussion Section, we pointed out key genes involved in these chromosomal alterations. Methods: Cytogenetic analysis was performed on 193 pediatric patients using G-banding and fluorescence in situ hybridization. Results: Abnormal karyotypes were observed in 43.5% (84/193) of patients, mainly in the advanced subtype. The main chromosomal alterations were monosomy 7 (−7) in 14% of the cases (12/84), deletion of the long arm of chromosome 11 [del(11q)] in 12% (10/84) and both trisomy 8 (+8) and deletion of the long arm of chromosome 7 [del(7q)] in 8% (7/84). Evolution from MDS to AML was observed in 22% of the patients (42/193), and it was associated with complex karyotypes, del(11q), −7/del(7q), and +8. Conclusions: Our results suggest that specific chromosomal alterations, such as del(11q), del(7q), and +8, may predict evolution to AML and might be considered high-risk cytogenetic markers in pMDS.

This study aimed to identify genetic variants using a customized next-generation sequencing (NGS) panel for pediatric myelodysplastic syndrome (pMDS) and to explore their associations with cytogenetic and clinical characteristics. Cytogenetic analyses were conducted using G-banding and fluorescence in situ hybridization. NGS was performed with the Ion Torrent Personal Genome Machine for the following genes: GATA2, RUNX1, CEBPA, ANKRD26, ETV6, SAMD9, SAMD9L, PTPN11, NRAS, SETBP1, DDX41, TP53, FLT3, SRP72, and JAK3. Analyses were performed with Ion Reporter 5.20.8.0 software. Genetic variants were classified using the dbSNP, 1000 Genomes, COSMIC, and Varsome databases. We analyzed 25 cases of pMDS; 15 presented abnormal karyotypes, and 19 showed genetic variants. Among the 29 variants identified across 12/15 genes, 27% were pathogenic and 14% were likely pathogenic, with NRAS and GATA2 most frequently associated with disease progression. A new somatic variant of uncertain significance in SETBP1 was detected in seven patients showing heterogeneous clinical outcomes. Genetic variants were found in 7/10 patients with normal karyotypes, indicating that submicroscopic alterations can shed light on disease biology. Our results highlight the critical role of a targeted NGS panel in identifying molecular alterations associated with pMDS pathogenesis, thereby enhancing diagnostic precision, prognosis, and aiding in treatment selection.

Myelodysplastic syndrome (MDS) comprises a heterogeneous group of clonal hematopoietic stem cell diseases, characterized by ineffective hematopoiesis, dysplastic cells, peripheral blood cytopenias,...